Polymorphic forms of metopimazine

ABSTRACT

Provided herein are novel polymorphic forms of metopimazine mesylate. These polymorphic forms are useful in methods, compositions, and kits for the treatment of an enteric nervous system disorder.

RELATED APPLICATION

This application claims the benefit of priority to U.S. ProvisionalPatent Application No. 63/003,998, filed Apr. 2, 2020, which applicationis hereby incorporated by reference in its entirety.

BACKGROUND

The enteric nervous system (ENS) comprises about one hundred millionneurons embedded in the lining of the gastrointestinal system. The ENSinnervates the gastrointestinal system, including the esophagus, thestomach (e.g., gastric area), and the intestines. Motor neurons of theENS control stomach muscle contractility, peristalsis, and churning ofintestinal contents. It has been estimated that about 50% of the body'sdopamine is found in the ENS.

Gastrointestinal (GI) tract disorders affect many people. Irritablebowel syndrome (IBS), a disorder in which the intestine functionsabnormally due to dysfunction of the muscles or nerves of the GI tract,affects 10 to 15% of the adult population. Symptoms of IBS includeconstipation, diarrhea, and abdominal pain. Functional dyspepsia(dyspepsia caused by a dysfunction of the muscles or nerves associatedwith the upper GI tract) affects 10 to 20% of the adult population.Gastroparesis, a disorder causing inadequate grinding of food by thestomach and delayed gastric emptying, affects up to 10% of the generalpopulation. Gastroesophageal reflux disorder (GERD), a chronic digestivedisease that occurs when stomach acid and/or bile backs up into theesophagus, has been estimated to affect up to 35% of infants in thefirst few months of life and more than half of the general population inthe US.

In addition, gastrointestinal disorders can be associated with a numberof other diseases. For example, some of the earliest symptoms ofParkinson's disease, a disorder characterized by neurodegeneration ofdopamine neurons, include, e.g., constipation and other gastrointestinalsymptoms, likely due to degeneration or dysfunction of ENS dopamineneurons. Another example is diabetes, one of the most common causes ofgastroparesis, as chronic high blood sugar can damage the vagus nervewhich modulates the enteric nervous system. Multiple sclerosis isanother disease that is associated with ENS disorders such as, e.g.,gastroparesis. Migraine headaches are commonly associated with gastricstasis. Chemotherapy-induced nausea and/or vomiting have been estimatedto affect 85% of cancer patients undergoing chemotherapy and can resultin discontinuation of treatment. If the chemotherapy-induced nauseaand/or vomiting are not properly managed, it can cause dehydration andpoor quality of life and may result in discontinuation of chemotherapy.

ENS dysfunction has been implicated in several of the disordersdescribed above. For example, impaired or dysfunctional ENS neuronalsignaling has been strongly implicated as a causative factor forgastroparesis.

There are currently no adequate treatments for these disorders. Forexample, IBS treatments lubiprostone and linaclotide are used to mimicinfectious diarrhea in order to treat constipation; however, theseagents do not correct the underlying ENS dysfunction and are marginallyeffective. The dopamine D2 receptor antagonists domperidone andmetoclopramide have been previously indicated for the treatment ofnausea and vomiting, however, their use is discouraged due tosignificant safety issues, in particular for extended periods of time.Two significant safety concerns relate to (1) unwanted cardiac sideeffects caused by, e.g., interaction of the agents with ion channelsinvolved in cardiac action potentials, and (2) unwanted motordysfunction caused by the actions of the dopamine antagonists whichcross the blood brain barrier into the brain. For example, it has beenestablished that many dopamine receptor antagonists inhibit hERGchannels (a type of potassium channel) to cause drug-induced long QTsyndrome, a heart condition characterized by abnormal cardiac actionpotential rhythms. Long QT syndrome can increase risk of cardiacarrhythmias, which may lead to sudden cardiac death. Indeed, thedopamine D2 antagonist domperidone has been shown to inhibit hERGactivity and increase risk of long QT syndrome, and increase risk ofsudden cardiac death. This has resulted in an FDA ban on the use ofdomperidone in the United States and an initiated review of the safetyof domperidone use by the European Medicines Agency. Metoclopramidecannot be taken for more than 12 weeks and has a black box warning forCNS-related side effects such as tardive dyskinesia, adifficult-to-treat and often incurable disorder characterized byinvoluntary, repetitive body movements.

SUMMARY OF THE APPLICATION

The present application provides a crystalline form of metopimazinemesylate. In certain embodiments, the crystalline form comprises lessthan 10 wt. % of amorphous forms. In certain embodiments, thecrystalline form is in non-solvate form. In certain such embodiments,the crystalline form comprises less than 10 wt. % of solvate forms. Incertain embodiments of the foregoing, the present application provides acrystalline form of metopimazine mesylate wherein the crystalline formcomprises metopimazine mesylate Crystal Form A.

The present application provides a crystalline form of metopimazinemesylate characterized by an X-ray powder diffraction pattern comprisinga peak at the following 2θ value: 18.75°. In certain embodiments, thecrystalline form of metopimazine mesylate is characterized by an X-raypowder diffraction pattern comprising a peak at the following 2θ value:15.91° and 18.75°. In certain embodiments, the crystalline form ofmetopimazine mesylate is characterized by an X-ray powder diffractionpattern comprising a peak at the following 2θ value: 15.91°, 18.75°, and24.44°.

The present application provides a crystalline form of metopimazinemesylate characterized by an X-ray powder diffraction pattern comprisingone or more of the following 2θ values: 9.37°, 15.26°, 15.91°, 18.75°,19.09°, 20.80°, 21.22°, 21.77°, and 24.44°. In certain embodiments, thecrystalline form is characterized by an X-ray powder diffraction patterncomprising two or more of the following 2θ values: 9.37°, 15.26°,15.91°, 18.75°, 19.09°, 20.80°, 21.22°, 21.77°, and 24.44°. In certainembodiments, the crystalline form is characterized by an X-ray powderdiffraction pattern comprising three or more of the following 2θ values:9.37′, 15.26°, 15.91°, 18.75°, 19.09°, 20.80°, 21.22°, 21.77°, and24.44°.

The present application provides a crystalline form of metopimazinemesylate characterized by a differential scanning calorimetry patterncomprising a single endotherm comprising an onset temperature range of208° C. to 212° C. In certain embodiments, the single endothermcomprises an onset temperature range of 208° C. to 211° C. In certainembodiments, the single endotherm comprises an onset temperature rangeof 209° C. to 210° C. In certain embodiments of any of the foregoing,the single endotherm comprises a peak temperature range of 213° C. to214° C. In certain embodiments of any of the foregoing, the singleendotherm comprises an enthalpy of transition of 95-100 J/g. In certainsuch embodiments, the single endotherm comprises an enthalpy oftransition of 96-98 J/g. In further embodiments, the single endothermcomprises an enthalpy of transition of 97-98 J/g.

The present application provides a crystalline form of metopimazinemesylate characterized by a thermogravimetric analysis profilecomprising a total weight loss of 0.4% up to 150.0° C.

In certain embodiments of any of the foregoing, the compositioncomprises less than 10 wt. % of other crystalline forms. In certain suchembodiments, the composition comprises less than 1 wt. % of othercrystalline forms. In certain embodiments of the foregoing, thecomposition comprises less than 10 wt. % of amorphous forms. In certainsuch embodiments, the composition comprises less than 1 wt. % ofamorphous forms.

The present application provides a pharmaceutical composition comprisingany of the foregoing crystalline forms and a pharmaceutically acceptableexcipient. In certain embodiments, the pharmaceutical composition issuitable for administering orally, intraduodenally, intracolonically,enterally, topically, intranasally, non-orally, buccally, sublingually,by inhalation, or rectally. In certain embodiments, the composition issuitable for administering orally. In certain embodiments, thecomposition is suitable for administering sublingually. In certainembodiments of the foregoing, the pharmaceutical composition isformulated as a tablet, a capsule, an oil, a gel, a paste, a powder, asuspension, a syrup, an enema, a suppository, an emulsion, or asolution, an extended-release formulation, or a modified-releaseformulation. In certain such embodiments, the composition is formulatedas an extended release formulation. In further embodiments, thecomposition is formulated as a capsule.

In certain embodiments of any of the foregoing pharmaceuticalcompositions, the composition comprises 5 mg of the crystalline form ofmetopimazine mesylate. In certain embodiments, the composition comprises10 mg of the crystalline form of metopimazine mesylate. In certainembodiments, the composition comprises 15 mg of the crystalline form ofmetopimazine mesylate. In certain embodiments, the composition comprises20 mg of the crystalline form of metopimazine mesylate.

In certain embodiments of any of the foregoing pharmaceuticalcompositions, the composition is suitable for administration one timeper day. In certain embodiments, the composition is suitable foradministration two times per day. In certain embodiments, thecomposition is suitable for administration three times per day. Incertain embodiments, the composition is suitable for administration fourtimes per day.

In certain embodiments of any of the foregoing pharmaceuticalcompositions, between about 5 mg and about 160 mg of the crystallineform of metopimazine mesylate is administered per day. In certainembodiments, the composition is suitable for administration of more than20 mg of the crystalline form of metopimazine mesylate per day.

The present application provides a method of treating an enteric nervoussystem disorder in a human subject in need thereof, comprisingadministering to the subject any of the foregoing pharmaceuticalcompositions. In certain embodiments, the enteric nervous systemdisorder is a chronic disorder. In other embodiments, the entericnervous system disorder is an acute disorder. In certain embodiments,the enteric nervous system disorder is selected from the groupconsisting of gastroparesis, Irritable Bowel Syndrome, lysosomal storagedisorders, intestinal dysmotility, ganglioneuroma, multiple endocrineneoplasia type 2B (MEN2B), gastrointestinal neuropathy, functionaldyspepsia, gastroesophageal reflux disease (GERD), and intestinalneuronal dysplasia. In certain embodiments of the foregoing, the entericnervous system disorder comprises a symptom selected from the groupconsisting of early satiety, post-prandial fullness, abdominal fullness,nausea, vomiting, delayed gastric emptying, diarrhea, abdominal pain,gas, bloating, gastroesophageal reflux, reduced appetite, andconstipation. In certain embodiments, the enteric nervous systemdisorder symptom comprises nausea. In other embodiments, the entericnervous system disorder symptom comprises vomiting.

The present application provides a method of treating gastroparesis in ahuman subject in need thereof, comprising administering to the subjectany of the foregoing pharmaceutical compositions. In certainembodiments, the gastroparesis is diabetic gastroparesis. In otherembodiments, the gastroparesis is idiopathic gastroparesis. In certainembodiments of the foregoing, the gastroparesis comprises a symptomselected from the group consisting of early satiety, post prandialfullness, abdominal fullness, nausea, vomiting, delayed gastricemptying, diarrhea, abdominal pain, gas, bloating, gastroesophagealreflux, reduced appetite, and constipation. In certain such embodiments,the gastroparesis symptom comprises nausea. In other embodiments, thegastroparesis symptom comprises vomiting.

The present application provides a method of treating nausea associatedwith gastroparesis in a human subject in need thereof, comprisingadministering to the subject any of the foregoing pharmaceuticalcompositions.

The present application provides a method of treating vomitingassociated with gastroparesis in a human subject in need thereof,comprising administering to the subject any of the foregoingpharmaceutical compositions.

The present application provides a method of improving gastric emptyingin a human subject in need thereof, comprising administering to thesubject any of the foregoing pharmaceutical compositions.

The present application provides a method of treating functional andmotility disorders of the GI tract in a human subject in need thereof,comprising administering to the subject any of the foregoingpharmaceutical compositions.

In certain embodiments of any of the foregoing methods, thepharmaceutical composition is administered to the subject chronically.In other embodiments of any of the foregoing methods, the pharmaceuticalcomposition is administered to the subject acutely.

In certain embodiments of any of the foregoing methods, thepharmaceutical composition is administered to the subject for at least 6days. In certain such embodiments, the pharmaceutical composition isadministered to the subject for at least 7 days. In certain embodiments,the subject for at least four weeks. In certain embodiments, thepharmaceutical composition is administered to the subject for at least12 weeks.

In certain embodiments of any of the foregoing methods, thepharmaceutical composition is administered to the subject one time perday. In certain embodiments, the pharmaceutical composition isadministered to the subject two times per day. In certain embodiments,the pharmaceutical composition is administered to the subject threetimes per day. In certain embodiments, the pharmaceutical composition isadministered to the subject four times per day.

In certain embodiments of any of the foregoing methods, between about 5mg and about 160 mg of the metopimazine mesylate is administered to thesubject per day. In certain such embodiments, more than 20 mg ofmetopimazine mesylate is administered to the subject per day.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 depicts the X-ray powder diffractogram (XRPD) of metopimazinemesylate Crystal Form A.

FIG. 2 depicts the thermogravimetric analysis (TGA) plot formetopimazine mesylate Crystal Form A.

FIG. 3 depicts the differential scanning calorimetry (DSC) plot formetopimazine mesylate Crystal Form A.

FIG. 4 depicts the X-ray powder diffractogram (XRPD) of metopimazinemesylate Crystal Form B.

FIG. 5 depicts the TGA and DSC plots for metopimazine mesylate CrystalForm B.

DETAILED DESCRIPTION OF THE APPLICATION

The present application provides a crystalline form of metopimazinemesylate,

In certain embodiments of the present application, the crystalline formof metopimazine mesylate comprises less than 10 wt. % of othercrystalline forms, such as less than 5 wt. %, less than 4 wt. %, lessthan 3 wt. %, less than 2 wt. %, less than 1 wt. %, less than 0.1 wt. %,or less than 0.01 wt. % of other crystalline forms.

In certain embodiments of the present application, the crystalline formof metopimazine mesylate comprises less than 10 wt. % of amorphousforms, such as less than 5 wt. %, less than 4 wt. less than 3 wt. %,less than 2 wt. %, less than 1 wt. %, less than 0.1 wt. %, or less than0.01 wt. % of amorphous forms.

In certain embodiments of the present application, the crystalline formof metopimazine mesylate comprises less than 10 wt. % of other forms(e.g., other crystalline forms of metopimazine mesylate or otheramorphous forms of metopimazine mesylate), such as less than 5 wt. %,less than 4 wt. %, less than 3 wt. %, less than 2 wt. %, less than 1 wt.%, less than 0.1 wt. %, or less than 0.01 wt. % of other forms (e.g.,other crystalline forms of metopimazine mesylate or other amorphousforms of metopimazine mesylate).

In certain embodiments of the present application, the crystalline formof metopimazine mesylate is in a non-solvate form. In certain suchembodiments of the present application, the crystalline form ofmetopimazine mesylate comprises less than 10 wt. % of solvate forms,such as less than 5 wt. %, less than 4 wt. %, less than 3 wt. %, lessthan 2 wt. %, less than 1 wt. %, less than 0.1 wt. %, or less than 0.01wt. % of solvate forms.

In certain embodiments of the present application, the crystalline formof metopimazine mesylate is in a non-hydrate form. In certain suchembodiments, the crystalline form of metopimazine mesylate includesbetween about 10% metopimazine mesylate non-hydrate and about 100%metopimazine mesylate non-hydrate. For example, the crystalline form ofmetopimazine mesylate includes about 10% metopimazine mesylatenon-hydrate, about 20% metopimazine mesylate non-hydrate, about 30%metopimazine mesylate non-hydrate, about 40% metopimazine mesylatenon-hydrate, about 50% metopimazine mesylate non-hydrate, about 60%metopimazine mesylate non-hydrate, about 70% metopimazine mesylatenon-hydrate, about 80% metopimazine mesylate non-hydrate, about 90%metopimazine mesylate non-hydrate, or about 95% metopimazine mesylatenon-hydrate. In certain such embodiments of the present application, thecrystalline form of metopimazine mesylate comprises less than 10 wt. %of hydrate forms, such as less than 5 wt. %, less than 4 wt. %, lessthan 3 wt. %, less than 2 wt. %, less than 1 wt. %, less than 0.1 wt. %,or less than 0.01 wt. % of hydrate forms.

In certain embodiments of the present application, the crystalline formof metopimazine mesylate is in a solvate form, such as a hydrate form(e.g., mono-hydrate form). In certain such embodiments, the crystallineform of metopimazine mesylate includes between about 10% metopimazinemesylate mono-hydrate and about 100% metopimazine mesylate mono-hydrate.For example, the crystalline form of metopimazine mesylate includesabout 10% metopimazine mesylate mono-hydrate, about 20% metopimazinemesylate non-hydrate, about 30% metopimazine mesylate mono-hydrate,about 40% metopimazine mesylate mono-hydrate, about 50% metopimazinemesylate mono-hydrate, about 60% metopimazine mesylate mono-hydrate,about 70% metopimazine mesylate mono-hydrate, about 80% metopimazinemesylate mono-hydrate, about 90% metopimazine mesylate mono-hydrate, orabout 95% metopimazine mesylate mono-hydrate. In certain suchembodiments of the present application, the crystalline form ofmetopimazine mesylate comprises less than 10 wt. % u of other solvateforms or non-solvate forms, such as less than 5 wt. %, less than 4 wt.%, less than 3 wt. %, less than 2 wt. %, less than 1 wt. %, less than0.1 wt. %, or less than 0.01 wt. % of other solvate forms or non-solvateforms.

The present application provides metopimazine mesylate Crystal Form A,

characterized by an X-ray powder diffraction (XRPD) pattern comprisingone or more of the 2-theta (20) values provided in Table 1. Thediffraction pattern was recorded with Cu, Kα radiation.

TABLE 1 Peaks identified on XRPD for metopimazine mesylate Crystal FormA Pos. Height FWHM Left d-spacing Rel. Int. [°2θ] [cts] [°2θ] [Å] [%]9.37 4920.97 0.1535 9.44 50.55 9.87 263.66 0.1023 8.96 2.71 14.33 157.710.1535 6.18 1.62 15.26 4020.53 0.1023 5.81 41.30 15.91 8116.56 0.10235.57 83.38 16.55 551.07 0.1023 5.36 5.66 17.52 2956.27 0.1023 5.06 30.3717.75 1422.83 0.1023 5.00 14.62 18.75 9734.71 0.1279 4.73 100.00 19.092488.96 0.1023 4.65 25.57 19.72 1116.67 0.1279 4.50 11.47 20.80 2397.360.1023 4.27 24.63 21.22 6352.12 0.1023 4.19 65.25 21.77 1801.77 0.10234.08 18.51 23.29 179.97 0.1023 3.82 1.85 23.91 2465.28 0.1023 3.72 25.3224.44 7334.27 0.1023 3.64 75.34 25.37 346.61 0.1023 3.51 3.56 26.392648.50 0.1023 3.38 27.21 26.92 265.75 0.1279 3.31 2.73 27.96 766.290.1023 3.19 7.87 28.23 980.13 0.1535 3.16 10.07 28.78 457.50 0.1279 3.104.70 29.27 115.22 0.1023 3.05 1.18 29.64 137.61 0.2558 3.01 1.41 30.67569.41 0.1023 2.92 5.85 31.29 166.89 0.1535 2.86 1.71 31.84 407.680.1023 2.81 4.19 32.09 647.44 0.1535 2.79 6.65 32.99 257.23 0.1279 2.722.64 33.40 118.31 0.1535 2.68 1.22 33.99 283.82 0.1023 2.64 2.92 35.91333.91 0.2047 2.50 3.43 36.80 388.57 0.1791 2.44 3.99 37.41 242.650.1535 2.40 2.49 37.92 565.14 0.1535 2.37 5.81 39.27 174.37 0.1279 2.291.79In certain embodiments, metopimazine mesylate Crystal Form A ischaracterized by an XRPD pattern comprising at least two 2θ valuesselected from those set forth in Table 1. In certain embodiments, themetopimazine mesylate Crystal Form A is characterized by an XRPD patterncomprising at least three, at least four, at least five, at least six,at least seven, at least eight, or at least nine 2θ values selected fromthose set forth in Table 1. In certain embodiments, the metopimazinemesylate Crystal Form A is characterized by one or more of the 2θ valuesin the range of from about 5 to about 25° 2θ in Table 1. In certainembodiments, the metopimazine mesylate Crystal Form A is characterizedby at least two of the 2θ values in the range of from about 5 to about25° 2θ in Table 1. In certain embodiments, the metopimazine mesylateCrystal Form A is characterized by at least three, at least four, atleast five, at least six, at least seven, at least eight, or at leastnine of the 2θ values in the range of from about 5 to about 25° 2θ inTable 1. In certain embodiments, the metopimazine mesylate Crystal FormA is characterized by an XRPD pattern comprising the 2θ values selectedfrom those set forth in Table 1. It will be appreciated by a personskilled in the art that the XRPD intensities may vary between differentsamples and different sample preparations for a variety of reasonsincluding preferred orientation. It will also be appreciated by a personskilled in the art that smaller shifts in the measured Angle and hencethe d-spacing may occur for a variety of reasons including variation ofSample Surface level in the diffractometer. It will further beappreciated by a person skilled in the art that the 2θ degrees providedin Table 1 will generally be reproducible to within a range of fromabout ±0.10 2θ degrees to about ±0.20 2θ degrees, with a preferred rangebeing about ±0.10 2θ degrees. See e.g., United States Pharmacopoeia XXV(2002), p. 2088-2089.

In certain embodiments, metopimazine mesylate Crystal Form A ischaracterized by an XRPD pattern comprising one or more of the following2θ values: 9.37°, 15.26°, 15.91°, 18.75°, 19.09°, 20.80°, 21.22°,21.77°, and 24.44°±0.10-0.20 2θ. In certain embodiments, metopimazinemesylate Crystal Form A is characterized by an XRPD) pattern comprisingtwo or more of the following 2θ values: 9.37°, 15.26°, 15.91°, 18.75°,19.09°, 20.80°, 21.22°, 21.77°, and 24.44°±0.10 0.20 2θ. In certainembodiments, metopimazine mesylate Crystal Form A is characterized by anXRPD pattern comprising three or more of the following 2θ values: 9.37°,15.26°, 15.91°, 18.75°, 19.09°, 20.80°, 21.22°, 21.77°, and24.44°±0.10-0.20 2θ. In certain embodiments, metopimazine mesylateCrystal Form A is characterized by an XRPD pattern comprising four ormore of the following 2θ values: 9.37°, 15.26°, 15.91°, 18.75°, 19.09°,20.80°, 21.22°, 21.77°, and 24.44°±0.10 0.20 2θ. In certain embodiments,metopimazine mesylate Crystal Form A is characterized by an XRPD patterncomprising five or more of the following 2θ values: 9.37°, 15.26°,15.91°, 18.75°, 19.09°, 20.80°, 21.22°, 21.77°, and 24.44°±0.10-0.20 2θ.

In certain embodiments, metopimazine mesylate Crystal Form A ischaracterized by an XRPD pattern comprising a peak at the following 2θvalue 18.75°±0.10-0.20 2θ. In certain embodiments, metopimazine mesylateCrystal Form A is characterized by an XRPD pattern comprising peaks atthe following 2θ values 15.91° and 18.75°±0.10-0.20 2θ. In certainembodiments, metopimazine mesylate Crystal Form A is characterized by anXRPD pattern comprising peaks at the following 2θ values 15.91°, 18.75°,and 24.44°±0.10-0.20 2θ. In certain embodiments, metopimazine mesylateCrystal Form A is characterized by an XRPD pattern comprising peaks atthe following 2θ values 15.91°, 18.75°, 21.22°, and 24.44°±0.10-0.20 2θ.In certain embodiments, metopimazine mesylate Crystal Form A ischaracterized by an XRPD pattern comprising peaks at the following 2θvalues 9.37°, 15.91°, 18.75°, 21.22°, and 24.44°±0.10-0.20 2θ. Incertain embodiments, metopimazine mesylate Crystal Form A ischaracterized by an XRPD pattern comprising peaks at the following 2θvalues 9.37°, 15.26°, 15.91°, 18.75°, 21.22°, and 24.44°±0.10-0.20 2θ.

The present application provides metopimazine mesylate Crystal Form A,characterized by an XRPD pattern comprising at least two D-spacingvalues selected from those set forth in Table 1. In certain embodiments,the metopimazine mesylate Crystal Form A is characterized by an XRPDpattern comprising at least three, at least four, at least five, or atleast six D-spacing values selected from those set forth in Table 1. Incertain embodiments, the metopimazine mesylate Crystal Form A ischaracterized by an XRPD pattern comprising the D-spacing valuesselected from those set forth in Table 1.

In certain embodiments, the metopimazine mesylate Crystal Form A ischaracterized by an XRPD pattern as set forth in Table 1. In certainembodiments, the metopimazine mesylate Crystal Form A exhibits an XRPDpattern as set forth in FIG. 1 .

In certain embodiments, the metopimazine mesylate Crystal Form A ischaracterized by a differential scanning calorimetry (DSC) patterncomprising a single endotherm with an onset temperature range of 208° C.to 212° C., or 208° C. to 211° C., such as 209° C. to 210° C. (e.g.,209.9° C.). In certain embodiments, the metopimazine mesylate CrystalForm A is characterized by a DSC pattern comprising a single endothermwith a peak temperature range of 213° C. to 214° C. (e.g., 213.1° C.).It will be appreciated by a person skilled in the art that the endothermgiven above and in FIG. 3 will typically be reproducible to within arange of from ±0.5 to 3° C., such as ±2° C., ±1° C., or ±0.5° C. Incertain embodiments, the metopimazine mesylate Crystal Form A ischaracterized by a DSC pattern comprising a single endotherm with anenthalpy of transition of 95-100 J/g, such as 96-98 J/g, 97-98 J/g, or97.5 J/g (e.g., 97.47 J/g). In certain embodiments, the metopimazinemesylate Crystal Form A is characterized by a DSC pattern as set forthin FIG. 3 .

In certain embodiments, the metopimazine mesylate Crystal Form A ischaracterized by a thermogravimetric analysis (TGA) profile with a totalweight loss of 0.4% (e.g., 0.42%) up to 150.0° C. In certainembodiments, the metopimazine mesylate Crystal Form A is characterizedby a TGA profile as set forth in FIG. 2 .

In certain embodiments of the present application, the metopimazinemesylate Crystal Form A comprises less than 10 wt. % of other crystalforms (e.g., metopimazine mesylate hydrate Crystal Form B), such as lessthan 5 wt. %, less than 4 wt. %, less than 3 wt. %, less than 2 wt. %,less than 1 wt. %, less than 0.1 wt. %, or less than 0.01 wt. % of othercrystal forms (e.g., metopimazine mesylate hydrate Crystal Form B).

In certain embodiments of the present application, the metopimazinemesylate Crystal Form A comprises less than 10 wt. % of amorphous forms,such as less than 5 wt. %, less than 4 wt. %, less than 3 wt. %, lessthan 2 wt. %, less than 1 wt. %, less than 0.1 wt. % u, or less than0.01 wt. % of amorphous forms.

In certain embodiments of the present application, metopimazine mesylateCrystal Form A comprises less than 10 wt. % of other forms (e.g., othercrystalline forms of metopimazine mesylate, such as metopimazinemesylate Crystal Form B, or other amorphous forms of metopimazinemesylate), such as less than 5 wt. %, less than 4 wt. %, less than 3 wt.%, less than 2 wt. %, less than 1 wt. %, less than 0.1 wt. %, or lessthan 0.01 wt. % of other forms (e.g., other crystalline forms ofmetopimazine mesylate, such as metopimazine mesylate Crystal Form B, orother amorphous forms of metopimazine mesylate).

In certain embodiments of the present application, the metopimazinemesylate Crystal Form A is in a non-solvate form. In certain suchembodiments of the present application, the metopimazine mesylateCrystal Form A comprises less than 10 wt. % of solvate forms, such asless than 5 wt. %, less than 4 wt. %, less than 3 wt. %, less than 2 wt.%, less than 1 wt. %, less than 0.1 wt. %, or less than 0.01 wt. % ofsolvate forms.

In certain embodiments of the present application, the metopimazinemesylate Crystal Form A is in a non-hydrate form. In certain suchembodiments of the present application, the metopimazine mesylateCrystal Form A comprises less than 10 wt. % of hydrate forms, such asless than 5 wt. %, less than 4 wt. %, less than 3 wt. %, less than 2 wt.%, less than 1 wt. %, less than 0.1 wt. %, or less than 0.01 wt. % ofhydrate forms.

The present application provides metopimazine mesylate hydrate CrystalForm B,

characterized by an XRPD pattern comprising one or more of the 20 valuesselected from those set forth in Table 2. The diffraction pattern wasrecorded with Cu, Kα radiation.

TABLE 2 Peaks identified on XRPD for metopimazine mesylate hydrateCrystal Form B Pos. Height FWHM Left d-spacing Rel. Int. [°2θ] [cts][°2θ] [Å] [%] 4.64 189.84 0.1023 19.06 14.72 8.57 131.03 0.1535 10.3110.16 10.71 363.36 0.2047 8.26 28.18 11.12 384.47 0.1023 7.96 29.8211.75 193.62 0.1535 7.53 15.02 12.51 266.85 0.3070 7.07 20.70 13.47184.58 0.1023 6.57 14.32 13.87 118.39 0.1535 6.38 9.18 15.82 359.170.1535 5.60 27.86 16.30 661.61 0.1023 5.44 51.31 16.90 1289.39 0.15355.25 100.00 17.29 205.33 0.1535 5.13 15.92 17.60 331.98 0.1023 5.0425.75 17.89 325.45 0.1023 4.96 25.24 18.42 899.37 0.2047 4.82 69.7518.88 506.01 0.1023 4.70 39.24 19.16 543.26 0.1535 4.63 42.13 20.00749.52 0.1535 4.44 58.13 20.66 212.79 0.1535 4.30 16.50 21.44 394.260.1535 4.14 30.58 22.02 439.23 0.1535 4.04 34.07 22.47 476.08 0.20473.96 36.92 23.21 519.15 0.1535 3.83 40.26 23.61 520.30 0.1023 3.77 40.3524.79 259.37 0.1023 3.59 20.12 25.51 700.65 0.1023 3.49 54.34 26.09158.11 0.1023 3.42 12.26 26.57 235.61 0.1535 3.36 18.27 27.12 309.010.1023 3.29 23.97 27.77 169.04 0.1535 3.21 13.11 28.39 168.22 0.10233.14 13.05 28.78 229.49 0.1535 3.10 17.80 32.94 117.10 0.2303 2.72 9.0836.31 80.65 0.2558 2.47 6.25In certain embodiments, metopimazine mesylate Crystal Form B ischaracterized by an XRPD pattern comprising at least two 2θ valuesselected from those set forth in Table 2. In certain embodiments, themetopimazine mesylate Crystal Form B is characterized by an XRPD patterncomprising at least three, at least four, at least five, at least six,at least seven, at least eight, or at least nine 2θ values selected fromthose set forth in Table 2. In certain embodiments, the metopimazinemesylate Crystal Form B is characterized by one or more of the 2θ valuesin the range of from about 5 to about 25′ 20 in Table 2. In certainembodiments, the metopimazine mesylate Crystal Form B is characterizedby at least two of the 2θ values in the range of from about 5 to about25′ 20 in Table 2. In certain embodiments, the metopimazine mesylateCrystal Form B is characterized by at least three, at least four, atleast five, at least six, at least seven, at least eight, or at leastnine of the 2θ values in the range of from about 5 to about 25° 2θ inTable 2 In certain embodiments, the metopimazine mesylate hydrateCrystal Form B is characterized by an XRPD pattern comprising the 2θvalues selected from those set forth in Table 2. It will further beappreciated by a person skilled in the art that the 2θ degrees providedin Table 2 will generally be reproducible to within a range of fromabout ±0.10 2θ degrees to about ±0.20 2θ degrees, with a preferred rangebeing about ±0.10 2θ degrees. See e.g., United States Pharmacopoeia XXV(2002), p. 2088-2089.

In certain embodiments, metopimazine mesylate Crystal Form B ischaracterized by an XRPD pattern comprising one or more of the following2θ values: 4.64°, 10.71°, 11.12°, 16.30°, 16.90°, 17.89°, 20.00°, and27.12°±0.10-0.20 2θ. In certain embodiments, metopimazine mesylateCrystal Form B is characterized by an XRPD pattern comprising two ormore of the following 20 values: 4.64°, 10.71°, 11.12°, 16.30°, 16.90°,17.89°, 20.00°, and 27.12°±0.10-0.20 2θ. In certain embodiments,metopimazine mesylate Crystal Form B is characterized by an XRPD patterncomprising three or more of the following 2θ values: 4.64°, 10.71°,11.12°, 16.30°, 16.90°, 17.89°, 20.00°, and 27.12°±0.10-0.20 2θ. Incertain embodiments, metopimazine mesylate Crystal Form B ischaracterized by an XRPD pattern comprising four or more of thefollowing 2θ values: 4.64°, 10.71°, 11.12°, 16.30°, 16.90°, 17.89°,20.00°, and 27.12°±0.10-0.20 2θ. In certain embodiments, metopimazinemesylate Crystal Form B is characterized by an XRPD pattern comprisingfive or more of the following 2θ values: 4.64°, 10.71°, 11.12°, 16.30°,16.90°, 17.89°, 20.00°, and 27.12°±0.10-0.20 2θ.

In certain embodiments, metopimazine mesylate Crystal Form B ischaracterized by an XRPD pattern comprising a peak at the following 2θvalue 16.90°±0.10-0.20 2θ. In certain embodiments, metopimazine mesylateCrystal Form B is characterized by an XRPD pattern comprising peaks atthe following 2θ values 16.90° and 20.00°±0.10-0.20 2θ. In certainembodiments, metopimazine mesylate Crystal Form B is characterized by anXRPD pattern comprising peaks at the following 2θ values 16.30°, 16.90°,and 20.00°±0.10-0.20 2θ. In certain embodiments, metopimazine mesylateCrystal Form B is characterized by an XRPD pattern comprising peaks atthe following 2θ values 11.12°, 16.30°, 16.90°, and 20.00°±0.10-0.20 2θ.In certain embodiments, metopimazine mesylate Crystal Form B ischaracterized by an XRPD pattern comprising peaks at the following 2θvalues 10.71°, 16.30°, 16.90°, and 20.00°±0.10-0.20 2θ. In certainembodiments, metopimazine mesylate Crystal Form B is characterized by anXRPD pattern comprising peaks at the following 2θ values 16.30°, 16.90°,17.89°, and 20.00°±0.10-0.20 2θ. In certain embodiments, metopimazinemesylate Crystal Form B is characterized by an XRPD pattern comprisingpeaks at the following 2θ values 16.30°, 16.90°, 20.00° and27.12°±0.10-0.20 2θ. In certain embodiments, metopimazine mesylateCrystal Form B is characterized by an XRPD pattern comprising peaks atthe following 2θ values 10.71°, 11.12°, 16.30°, 16.90°, and20.00°±0.10-0.20 20. In certain embodiments, metopimazine mesylateCrystal Form B is characterized by an XRPD pattern comprising peaks atthe following 2θ values 10.71°, 11.12°, 16.30°, 16.90°, 17.89°, 20.00°and 27.12°±0.10-0.20 2θ.

The present application provides metopimazine mesylate hydrate CrystalForm B, characterized by an XRPD pattern comprising at least twoD-spacing values selected from those set forth in Table 2. In certainembodiments, the metopimazine mesylate hydrate Crystal Form B ischaracterized by an XRPD pattern comprising at least three, at leastfour, at least five, or at least six D-spacing values selected fromthose set forth in Table 2. In certain embodiments, the metopimazinemesylate hydrate Crystal Form B is characterized by an XRPD patterncomprising the D-spacing values selected from those set forth in Table2.

In certain embodiments, the metopimazine mesylate hydrate Crystal Form Bis characterized by an XRPD pattern as set forth in Table 2.

In certain embodiments, the metopimazine mesylate Crystal Form B ischaracterized by a DSC pattern comprising two endothermic peaks and asingle exothermic peak. In certain such embodiments, the metopimazinemesylate Crystal Form B is characterized by a DSC pattern comprising afirst endothermic peak having an onset temperature range of 122° C. to125° C., or 123° C. to 124° C. (e.g., 123.5° C.). In certainembodiments, the metopimazine mesylate Crystal Form B is characterizedby a DSC pattern comprising a first endotherm with a peak temperaturerange of 125° C. to 127° C., such as 126° C. to 127° C. (e.g., 126.1°C.). In certain such embodiments, the metopimazine mesylate Crystal FormB is characterized by a DSC pattern comprising a first endotherm with anenthalpy of transition of 81-86 J/g, such as 82-85 J/g, 83-84 J/g, or83.5 J/g (e.g., 83.47 J/g). In certain such embodiments, themetopimazine mesylate Crystal Form B is characterized by a DSC patterncomprising a second endothermic peak having an onset temperature rangeof 207° C. to 210° C., or 208° C. to 209° C. (e.g., 208.6° C.). Incertain embodiments, the metopimazine mesylate Crystal Form B ischaracterized by a DSC pattern comprising a second endotherm with a peaktemperature range of 210° C. to 212° C., such as 211° C. to 212° C.(e.g., 211.2° C.). In certain such embodiments, the metopimazinemesylate Crystal Form B is characterized by a DSC pattern comprising asecond endotherm with an enthalpy of transition of 82-87 J/g, such as83-86 J/g, 84-85 J/g, or 84.5 J/g (e.g., 84.48 J/g). In certain suchembodiments, the metopimazine mesylate Crystal Form B is characterizedby a DSC pattern comprising a single exothermic peak with a peaktemperature range of 143° C. to 146° C., such as 144° C. to 145° C.(e.g., 144.6° C.). It will be appreciated by a person skilled in the artthat the endotherms and exotherm given above and in FIG. 5 willtypically be reproducible to within a range of from ±0.5 to 3° C., suchas ±2° C., ±1° C., or ±0.5° C. In certain embodiments, the metopimazinemesylate Crystal Form B is characterized by a DSC pattern as set forthin FIG. 5 .

In certain embodiments, the metopimazine mesylate Crystal Form B ischaracterized by a TGA profile with a total weight loss of 5.5-6% (e.g.,5.8%) up to 180.0° C. In certain embodiments, the metopimazine mesylateCrystal Form B is characterized by a TGA profile as set forth in FIG. 5.

In certain embodiments of the present application, the metopimazinemesylate hydrate Crystal Form B comprises less than 10 wt. % of othercrystal forms (e.g., metopimazine mesylate Crystal Form A), such as lessthan 5 wt. %, less than 4 wt. %, less than 3 wt. %, less than 2 wt. %,less than 1 wt. %, less than 0.1 wt. %, or less than 0.01 wt. % of othercrystal forms (e.g., metopimazine mesylate Crystal Form A).

In certain embodiments of the present application, the metopimazinemesylate hydrate Crystal Form B comprises less than 10 wt. % ofamorphous forms, such as less than 5 wt. %, less than 4 wt. %, less than3 wt. %, less than 2 wt. %, less than 1 wt. %, less than 0.1 wt. %, orless than 0.01 wt. % of amorphous forms.

In certain embodiments of the present application, metopimazine mesylateCrystal Form B comprises less than 10 wt. % of other forms (e.g., othercrystalline forms of metopimazine mesylate, such as metopimazinemesylate Crystal Form A, or other amorphous forms of metopimazinemesylate), such as less than 5 wt. %, less than 4 wt. %, less than 3 wt.%, less than 2 wt. %, less than 1 wt. %, less than 0.1 wt. %, or lessthan 0.01 wt. % of other forms (e.g., other crystalline forms ofmetopimazine mesylate, such as metopimazine mesylate Crystal Form A, orother amorphous forms of metopimazine mesylate).

In certain embodiments of the present application, the metopimazinemesylate Crystal Form B is in mono-hydrate form. In certain suchembodiments of the present application, the metopimazine mesylateCrystal Form B comprises less than 10 wt. % of other solvate forms ornon-solvate forms, such as less than 5 wt. %, less than 4 wt. %, lessthan 3 wt. %, less than 2 wt. %, less than 1 wt. % u, less than 0.1 wt.%, or less than 0.01 wt. % of other solvate forms or non-solvate forms.

The present application provides a pharmaceutical composition comprisingmetopimazine mesylate Crystal Form A, and a pharmaceutically acceptablecarrier. In certain such embodiments, the pharmaceutical compositionincludes between about 10% metopimazine mesylate Crystal Form A andabout 100% metopimazine mesylate Crystal Form A. For example, thepharmaceutical composition includes about 10% metopimazine mesylateCrystal Form A, about 20% metopimazine mesylate Crystal Form A, about30% metopimazine mesylate Crystal Form A, about 40% metopimazinemesylate Crystal Form A, about 50% metopimazine mesylate Crystal Form A,about 60% metopimazine mesylate Crystal Form A, about 70% metopimazinemesylate Crystal Form A, about 80% metopimazine mesylate Crystal Form A,about 90% metopimazine mesylate Crystal Form A, or about 95%metopimazine mesylate Crystal Form A.

In certain embodiments of the present application, pharmaceuticalcomposition comprising metopimazine mesylate Crystal Form A comprisesless than 10 wt. % of other forms of metopimazine mesylate (e.g., othercrystalline forms of metopimazine mesylate, such as metopimazinemesylate Crystal Form B, or other amorphous forms of metopimazinemesylate), such as less than 5 wt. %, less than 4 wt. %, less than 3 wt.%, less than 2 wt. %, less than 1 wt. %, less than 0.1 wt. %, or lessthan 0.01 wt. % of other forms of metopimazine mesylate (e.g., othercrystalline forms of metopimazine mesylate, such as metopimazinemesylate Crystal Form B, or other amorphous forms of metopimazinemesylate).

The present application provides a pharmaceutical composition comprisingmetopimazine mesylate Crystal Form B, and a pharmaceutically acceptablecarrier. In certain such embodiments, the pharmaceutical compositionincludes between about 10% metopimazine mesylate Crystal Form B andabout 100% metopimazine mesylate Crystal Form B. For example, thepharmaceutical composition includes about 10% metopimazine mesylateCrystal Form B, about 20% metopimazine mesylate Crystal Form B, about30% metopimazine mesylate Crystal Form B, about 40% metopimazinemesylate Crystal Form B, about 50% metopimazine mesylate Crystal Form B,about 60% metopimazine mesylate Crystal Form B, about 70% metopimazinemesylate Crystal Form B, about 80% metopimazine mesylate Crystal Form B,about 90% metopimazine mesylate Crystal Form B, or about 95%metopimazine mesylate Crystal Form B.

In certain embodiments of the present application, pharmaceuticalcomposition comprising metopimazine mesylate Crystal Form B comprisesless than 10 wt. % of other forms of metopimazine mesylate (e.g., othercrystalline forms of metopimazine mesylate, such as metopimazinemesylate Crystal Form A, or other amorphous forms of metopimazinemesylate), such as less than 5 wt. %, less than 4 wt. %, less than 3 wt.%, less than 2 wt. %, less than 1 wt. %, less than 0.1 wt. %, or lessthan 0.01 wt. % of other forms of metopimazine mesylate (e.g., othercrystalline forms of metopimazine mesylate, such as metopimazinemesylate Crystal Form A, or other amorphous forms of metopimazinemesylate).

In certain embodiments of any of the pharmaceutical compositionscomprising a crystalline form of metopimazine mesylate (e.g.,metopimazine mesylate Crystal Form A or metopimazine mesylate CrystalForm B) as described herein, the composition is suitable foradministering orally, intraduodenally, intracolonically, parenterally,enterally, intraperitoneally, topically, transdermally, ophthalmically,intranasally, locally, non-orally, via spray, subcutaneously,intravenously, intratonsillary, intramuscularly, buccally, sublingually,rectally, intra-arterially, by infusion, or intrathecally. In certainembodiments, the composition is suitable for administering orally. Incertain embodiments, the composition is suitable for administeringsublingually.

In certain embodiments of any of the pharmaceutical compositionscomprising a crystalline form of metopimazine mesylate (e.g.,metopimazine mesylate Crystal Form A or metopimazine mesylate CrystalForm B) as described herein, the pharmaceutical composition isformulated as a tablet, a capsule, a cream, a lotion, an oil, anointment, a gel, a paste, a powder, a suspension, a syrup, an enema, asuppository, an emulsion, or a solution, an extended-releaseformulation, or a modified-release formulation. In certain embodiments,the composition is formulated as an extended release formulation. Incertain embodiments, the composition is formulated as a capsule.

In certain embodiments of any of the pharmaceutical compositionscomprising a crystalline form of metopimazine mesylate (e.g.,metopimazine mesylate Crystal Form A or metopimazine mesylate CrystalForm B) as described herein, the composition comprises 5 mg of themetopimazine mesylate. In certain embodiments of any of the foregoingpharmaceutical compositions comprising a crystalline form ofmetopimazine mesylate (e.g., metopimazine mesylate Crystal Form A ormetopimazine mesylate Crystal Form B), the composition comprises 10 mgof the crystalline form of metopimazine mesylate (e.g., metopimazinemesylate Crystal Form A or metopimazine mesylate Crystal Form B). Incertain embodiments of any of the foregoing pharmaceutical compositionscomprising a crystalline form of metopimazine mesylate (e.g.,metopimazine mesylate Crystal Form A or metopimazine mesylate CrystalForm B), the composition comprises 15 mg of the crystalline form ofmetopimazine mesylate (e.g., metopimazine mesylate Crystal Form A ormetopimazine mesylate Crystal Form B). In certain embodiments of any ofthe foregoing pharmaceutical compositions comprising a crystalline formof metopimazine mesylate (e.g., metopimazine mesylate Crystal Form A ormetopimazine mesylate Crystal Form B), the composition comprises 20 mgof the crystalline form of metopimazine mesylate (e.g., metopimazinemesylate Crystal Form A or metopimazine mesylate Crystal Form B).

In certain embodiments of any of the pharmaceutical compositionscomprising a crystalline form of metopimazine mesylate (e.g.,metopimazine mesylate Crystal Form A or metopimazine mesylate CrystalForm B) as described herein, the composition is suitable foradministration one time per day. In other embodiments of any of theforegoing pharmaceutical compositions comprising a crystalline form ofmetopimazine mesylate (e.g., metopimazine mesylate Crystal Form A ormetopimazine mesylate Crystal Form B), the composition is suitable foradministration two times per day. In certain embodiments of any of theforegoing pharmaceutical compositions comprising a crystalline form ofmetopimazine mesylate (e.g., metopimazine mesylate Crystal Form A ormetopimazine mesylate Crystal Form B), the composition is suitable foradministration three times per day. In other embodiments of any of theforegoing pharmaceutical compositions comprising a crystalline form ofmetopimazine mesylate (e.g., metopimazine mesylate Crystal Form A ormetopimazine mesylate Crystal Form B), the composition is suitable foradministration four times per day.

In certain embodiments of any of the pharmaceutical compositionscomprising a crystalline form of metopimazine mesylate (e.g.,metopimazine mesylate Crystal Form A or metopimazine mesylate CrystalForm B) as described herein, between about 5 mg and about 160 mg of thecrystalline form of metopimazine mesylate (e.g., metopimazine mesylateCrystal Form A or metopimazine mesylate Crystal Form B) is administeredper day. In certain embodiments of any of the pharmaceuticalcompositions comprising a crystalline form of metopimazine mesylate(e.g., metopimazine mesylate Crystal Form A or metopimazine mesylateCrystal Form B) as described herein, between about 5 mg and about 240 mgof the crystalline form of metopimazine mesylate (e.g., metopimazinemesylate Crystal Form A or metopimazine mesylate Crystal Form B) isadministered per day, such as about 5 mg, about 10 mg, about 15 mg,about 20 mg, about 30 mg, about 40 mg, about 50 mg, about 60 mg, about80 mg, about 90 mg, about 100 mg, about 120 mg, about 150 mg, about 160mg, about 180 mg, about 200 mg, about 240 mg of the crystalline form ofmetopimazine mesylate (e.g., metopimazine mesylate Crystal Form A ormetopimazine mesylate Crystal Form B) is administered per day. Incertain embodiments of any of the pharmaceutical compositions comprisinga crystalline form of metopimazine mesylate (e.g., metopimazine mesylateCrystal Form A or metopimazine mesylate Crystal Form B) as describedherein, the composition is suitable for administration of more than 20mg of the crystalline form of metopimazine mesylate (e.g., metopimazinemesylate Crystal Form A or metopimazine mesylate Crystal Form B) perday. In certain embodiments of any of the pharmaceutical compositionscomprising a crystalline form of metopimazine mesylate (e.g.,metopimazine mesylate Crystal Form A or metopimazine mesylate CrystalForm B) as described herein, the composition is suitable foradministration of more than 30 mg of the crystalline form ofmetopimazine mesylate (e.g., metopimazine mesylate Crystal Form A ormetopimazine mesylate Crystal Form B) per day.

The present application provides a method of treating an enteric nervoussystem disorder in a human subject in need thereof, comprisingadministering to the subject a pharmaceutical composition comprising acrystalline form of metopimazine mesylate (e.g., metopimazine mesylateCrystal Form A or metopimazine mesylate Crystal Form B) as disclosedherein. In certain embodiments, the enteric nervous system disorder is achronic disorder. In certain embodiments, the enteric nervous systemdisorder is an acute disorder. In certain embodiments, the entericnervous system disorder is selected from the group consisting ofgastroparesis, Irritable Bowel Syndrome, lysosomal storage disorders,intestinal dysmotility, ganglioneuroma, multiple endocrine neoplasiatype 2B (MEN2B), gastrointestinal neuropathy, functional dyspepsia,gastroesophageal reflux disease (GERD), and intestinal neuronaldysplasia.

In certain embodiments, the enteric nervous system disorder comprises asymptom selected from the group consisting of early satiety,post-prandial fullness, abdominal fullness, nausea, vomiting, delayedgastric emptying, diarrhea, abdominal pain, gas, bloating,gastroesophageal reflux, reduced appetite, and constipation. In certainembodiments, the enteric nervous system disorder symptom comprisesnausea. In certain embodiments, the enteric nervous system disordersymptom comprises vomiting.

The present application provides a method of treating gastroparesis in ahuman subject in need thereof, comprising administering to the subject apharmaceutical composition comprising a crystalline form of metopimazinemesylate (e.g., metopimazine mesylate Crystal Form A or metopimazinemesylate Crystal Form B) as disclosed herein. In certain embodiments,the gastroparesis is diabetic gastroparesis. In certain embodiments, thegastroparesis is idiopathic gastroparesis. In certain embodiments, thegastroparesis comprises a symptom selected from the group consisting ofearly satiety, post-prandial fullness, abdominal fullness, nausea,vomiting, delayed gastric emptying, diarrhea, abdominal pain, gas,bloating, gastroesophageal reflux, reduced appetite, and constipation.In certain embodiments, the gastroparesis symptom comprises nausea. Incertain embodiments, the gastroparesis symptom comprises vomiting.

The present application provides a method of treating nausea associatedwith gastroparesis in a human subject in need thereof, comprisingadministering to the subject a pharmaceutical composition comprising acrystalline form of metopimazine mesylate (e.g., metopimazine mesylateCrystal Form A or metopimazine mesylate Crystal Form B) as disclosedherein.

The present application provides a method of treating vomitingassociated with gastroparesis in a human subject in need thereof,comprising administering to the subject a pharmaceutical compositioncomprising a crystalline form of metopimazine mesylate (e.g.,metopimazine mesylate Crystal Form A or metopimazine mesylate CrystalForm B) as disclosed herein.

The present application provides a method of improving gastric emptyingin a human subject in need thereof, comprising administering to thesubject a pharmaceutical composition comprising a crystalline form ofmetopimazine mesylate (e.g., metopimazine mesylate Crystal Form A ormetopimazine mesylate Crystal Form B) as disclosed herein.

The present application provides a method of treating functional andmotility disorders of the GI tract in a human subject in need thereof,comprising administering to the subject a pharmaceutical compositioncomprising a crystalline form of metopimazine mesylate (e.g.,metopimazine mesylate Crystal Form A or metopimazine mesylate CrystalForm B) as disclosed herein.

In certain embodiments of any of the methods disclosed herein, thepharmaceutical composition is administered to the subject chronically.In other embodiments of any of the methods disclosed herein, thepharmaceutical composition is administered to the subject acutely. Incertain embodiments of any of the methods disclosed herein, thepharmaceutical composition is administered to the subject for at least 6days. In certain embodiments of any of the methods disclosed herein, thepharmaceutical composition is administered to the subject for at least 7days. In certain such embodiments, wherein the pharmaceuticalcomposition is administered to the subject for at least four weeks. Incertain further embodiments, wherein the pharmaceutical composition isadministered to the subject for at least 12 weeks.

In certain embodiments of any of the methods disclosed herein, thepharmaceutical composition is administered to the subject one time perday. In certain embodiments, the pharmaceutical composition isadministered to the subject two times per day. In certain embodiments,the pharmaceutical composition is administered to the subject threetimes per day. In certain embodiments, the pharmaceutical composition isadministered to the subject four times per day.

In certain embodiments of any of the methods disclosed herein, betweenabout 5 mg and about 160 mg of the crystalline form of metopimazinemesylate (e.g., metopimazine mesylate Crystal Form A or metopimazinemesylate Crystal Form B) is administered to the subject per day. Incertain embodiments of any of the methods disclosed herein, more than 20mg of a crystalline form of metopimazine mesylate (e.g., metopimazinemesylate Crystal Form A or metopimazine mesylate Crystal Form B) isadministered to the subject per day. In certain embodiments of any ofthe methods disclosed herein, more than 30 mg of a crystalline form ofmetopimazine mesylate (e.g., metopimazine mesylate Crystal Form A ormetopimazine mesylate Crystal Form B) is administered to the subject perday. In certain embodiments of any of the methods as described herein,between about 5 mg and about 240 mg of the crystalline form ofmetopimazine mesylate (e.g., metopimazine mesylate Crystal Form A ormetopimazine mesylate Crystal Form B) is administered to the subject perday, such as about 5 mg, about 10 mg, about 15 mg, about 20 mg, about 30mg, about 40 mg, about 50 mg, about 60 mg, about 80 mg, about 90 mg,about 100 mg, about 120 mg, about 150 mg, about 160 mg, about 180 mg,about 200 mg, about 240 mg of the crystalline form of metopimazinemesylate (e.g., metopimazine mesylate Crystal Form A or metopimazinemesylate Crystal Form B) is administered to the subject per day. Incertain embodiments of any of the methods disclosed herein, about 5 mgof the crystalline form of metopimazine mesylate (e.g., metopimazinemesylate Crystal Form A or metopimazine mesylate Crystal Form B) isadministered to the subject one time, two times, three times, or fourtimes per day. In certain embodiments of any of the methods disclosedherein, about 10 mg, about 15 mg, about 20 mg, about 30 mg, about 40 mg,about 50 mg, or about 60 mg of the crystalline form of metopimazinemesylate (e.g., metopimazine mesylate Crystal Form A or metopimazinemesylate Crystal Form B) is administered to the subject one time, twotimes, three times, or four times per day. In certain embodiments of anyof the methods disclosed herein, about 40 mg of a crystalline form ofmetopimazine mesylate (e.g., metopimazine mesylate Crystal Form A ormetopimazine mesylate Crystal Form B) is administered to the subjectfour times per day. In certain embodiments of any of the methodsdisclosed herein, about 60 mg of a crystalline form of metopimazinemesylate (e.g., metopimazine mesylate Crystal Form A or metopimazinemesylate Crystal Form B) is administered to the subject four times perday.

Definitions

As used in the specification and claims, the singular forms “a”, “an”and “the” include plural references unless the context clearly dictatesotherwise. For example, the term “a cell” includes a plurality of cells,including mixtures thereof.

The term “agonist,” as used herein, generally refers to a molecule suchas a compound, a drug, an enzyme activator or a hormone modulator thatbinds to a specific receptor and triggers a response in the cell. Anagonist generally mimics the action of an endogenous ligand (such a,e.g., dopamine) that binds to the same receptor.

The term “amorphous,” as used herein, refers to solids of disorderedarrangements of molecules that do not possess a distinguishable crystallattice.

The term “antagonist,” as used herein, refers to a molecule such as acompound, which diminishes, inhibits, or prevents a cellular response toa receptor activated by an agonist. Antagonists can include, but are notlimited to, competitive antagonists, non-competitive antagonists,uncompetitive antagonists, partial agonists and inverse agonists.Competitive antagonists can reversibly bind to receptors at the samebinding site (active site) as the endogenous ligand or agonist, withoutnecessarily activating the receptor. Non-competitive antagonists (alsoknown as allosteric antagonists) can bind to a distinctly separatebinding site from the agonist, exerting their action to that receptorvia another binding site. Non-competitive antagonists generally do notcompete with agonists for binding. Binding of a non-competitiveantagonist to the receptor may result in a decreased affinity of anagonist to that receptor. Alternatively, binding of a non-competitiveantagonist to a receptor may prevent a conformational change in thereceptor required for agonist-mediated receptor activation.Uncompetitive antagonists may require receptor activation by an agonistbefore they can bind to a separate allosteric binding site. Partialagonists can refer to molecules which, at a given receptor, might differin the amplitude of the functional response that they elicit aftermaximal receptor occupancy. Although they are agonists, partial agonistscan act as a competitive antagonist if co-administered with a fullagonist, as it competes with the full agonist for receptor occupancy andproducing a net decrease in the receptor activation observed with thefull agonist alone. An inverse agonist can have effects similar to anantagonist, but causes a distinct set of downstream biologicalresponses. Constitutively active receptors which exhibit intrinsic orbasal activity can have inverse agonists, which not only block theeffects of binding agonists like a classical antagonist, but alsoinhibit the basal activity of the receptor.

As use herein, the term “crystal” or “crystals” or “crystalline” or“crystalinic” refers to any solid that has a short or long range orderof the molecules, atoms or ions in a fixed lattice arrangement. SaltCrystals of the Present Invention may be in a single crystal form.Therefore, the Salt Crystals of the Present Invention may be in atriclinic, monoclinic, orthorhombic, tetragonal, rhobohedral, hexagonalor cubic crystal form or mixtures thereof. In particular, the SaltCrystals of the Present Invention are dry crystalline form.

As used herein, “gastrointestinal (GI) tract” refers to portions of thedigestive tract where substantial absorption is observed. As one ofskill would readily appreciate, substantial absorption is generallyobserved in the oral cavity, small intestine (e.g., duodenum, jejunum,and ileum), and large intestine (e.g., colon).

As used herein, “metopimazine mesylate” refers toI-(3-(2-(methylsulfonyl)-1OH-phenothiazin-10-yl)propyl)piperidine-4-carboxamide methanesulfonicacid.

As used herein, the “oral cavity” generally refers to the mouth andincludes the lips, the lining inside the cheeks and lips, the tongue,the upper and lower gums, the floor of the mouth under the tongue, thesublingual mucosa, the roof of the mouth, and the area behind the wisdomteeth.

As used herein, a compound that is “peripherally restricted” generallyrefers to a compound that does not substantially cross an intact bloodbrain barrier of a subject. The term also encompasses compounds that maycross an intact blood brain barrier, but upon administration to asubject is rapidly metabolized to a form that does not substantiallycross an intact blood brain barrier of the subject. A compound may beconsidered “peripherally restricted” if, upon administration to asubject, less than 50%, less than 45%, less than 40%, less than 35%,less than 30%, less than 25%, less than 20%, less than 15%, less than10%, less than 9%, less than 8%, less than 7%, less than 6%, less than5%, less than 4%, less than 3%, less than 2%, less than 1%, less than0.5%, less than 0.1% of the compound crosses an intact blood brainbarrier of the subject.

The term “solvate” refers to crystalline solid adducts containing eitherstoichiometric or nonstoichiometric amounts of a solvent incorporatedwithin the crystal structure. Therefore, the term “non-solvate” formherein refers to salt crystals that are free or substantially free ofsolvent molecules within the crystal structures of the invention.Similarly, the term “non-hydrate form herein refers to salt crystalsthat are free or substantially free of water molecules within thecrystal structures of the invention.

As used herein, the terms “treatment” or “treating” are usedinterchangeably herein. These terms refer to an approach for obtainingbeneficial or desired results including but not limited to a therapeuticbenefit and/or a prophylactic benefit. A therapeutic benefit can meaneradication or amelioration of the underlying disorder being treated.Also, a therapeutic benefit can be achieved with the eradication oramelioration of one or more of the physiological symptoms associatedwith the underlying disorder such that an improvement is observed in thesubject, notwithstanding that the subject may still be afflicted withthe underlying disorder. A prophylactic effect includes delaying oreliminating the appearance of a disease or condition, delaying oreliminating the onset of symptoms of a disease or condition, slowing,halting, or reversing the progression of a disease or condition, or anycombination thereof. For prophylactic benefit, the compositions may beadministered to a subject at risk of developing a particular disease, orto a subject reporting one or more of the physiological symptoms of adisease, even though a diagnosis of this disease may not have been made.

A “sub-therapeutic amount” of an agent is an amount less than theeffective amount for that agent. When combined with an effective orsub-therapeutic amount of one or more additional agents, thesub-therapeutic amount can produce a result desired by the physician,due to, for example, synergy in the resulting efficacious effects, orreduced adverse effects.

A “synergistically effective” therapeutic amount or “synergisticallyeffective” amount of an agent or therapy is an amount which, whencombined with an effective or sub-therapeutic amount of one or moreadditional agents, produces a greater effect than when either of theagents are used alone. In some embodiments, a synergistically effectivetherapeutic amount of an agent or therapy produces a greater effect whenused in combination than the additive effects of any of the individualagents when used alone. The term “greater effect” encompasses not only areduction in symptoms of the disorder to be treated, but also animproved side effect profile, improved tolerability, improved patientcompliance, improved efficacy, or any other improved clinical outcome.

The term “co-administration,” “administered in combination with,” andtheir grammatical equivalents, as used herein, encompass administrationof two or more agents to an animal so that both agents and/or theirmetabolites are present in the subject at the same time.Co-administration includes simultaneous administration in separatecompositions, administration at different times in separatecompositions, or administration in a composition in which both agentsare present.

The terms “determining”, “measuring”, “evaluating”, “assessing,”“assaying,” and “analyzing” are used interchangeably herein to refer toany form of measurement, and include determining if an element ispresent or not. These terms include both quantitative and/or qualitativedeterminations. Assessing may be relative or absolute. “Assessing thepresence of” includes determining the amount of something present, aswell as determining whether it is present or absent.

Exemplary Subjects

The pharmaceutical compositions as disclosed herein can be used for thetreatment of a disorder in a subject in need thereof. The subject may besuffering from, may be diagnosed with, may be exhibiting a symptom of,or may be suspected of having the disorder. The disorder can be agastrointestinal disorder, an enteric nervous system disorder, or otherdisorder. The disorder may be characterized by a hypomotility of atleast a portion of the gastrointestinal tract. For example, the disordercan be characterized by hypomotility of the stomach and/or intestine.The hypomotility may be caused by aberrant ENS neuronal signaling, forexample, by aberrant dopamine signaling activity.

In some embodiments, the enteric nervous system disorder isgastroparesis. The terms “gastroparesis” and “delayed gastric emptying”are used interchangeably herein to refer to a disorder that, e.g., slowsor stops the movement of food from the stomach to the small intestine.Normally, the muscles of the stomach, which are controlled by the vagusnerve, contract to break up food and move it through thegastrointestinal (GI) tract. Gastroparesis can occur, for example, whenthe vagus nerve is damaged by illness or injury, causing the stomachmuscles stop working normally. In subjects with gastroparesis, food canmove slowly from the stomach to the small intestine or may stop movingaltogether. Accordingly, the subject may be suffering from, may bediagnosed with, may be exhibiting a symptom of, or may be suspected ofhaving gastroparesis.

A subject may be suspected of having gastroparesis if the subjectexhibits or has exhibited a symptom of gastroparesis. Symptoms ofgastroparesis can include gastroesophageal reflux (GER), also calledacid reflux or acid regurgitation. Gastroesophageal reflux generallyrefers to a condition in which stomach contents flow back up into theesophagus. Other symptoms associated with gastroparesis include, but arenot limited to, early satiety, postprandial fullness, abdominalfullness, abdominal pain and/or burning sensation in the stomach area,abdominal bloating, lack of appetite, anorexia, malnutrition, nausea,and vomiting. A symptom of gastroparesis can be mild, moderate orsevere, and can occur frequently or infrequently. A symptom ofgastroparesis can vary in severity over time in the same subject.Accordingly, the subject may exhibit or has exhibited GER, earlysatiety, postprandial fullness, abdominal fullness, abdominal painand/or burning sensation in the stomach area, abdominal bloating, lackof appetite, anorexia, malnutrition, nausea, and/or vomiting.

The subject may be diagnosed with gastroparesis. Gastroparesis may bediagnosed by any means known to those of skill in the art or otherwisedescribed herein. Gastroparesis may be diagnosed, e.g., through aphysical exam, medical history, blood tests, tests to rule out blockageor structural problems in the GI tract, gastric emptying assays, andassays of GI contractile activity. Tests may also identify a nutritionaldisorder or underlying disease. Tests that are useful in diagnosinggastroparesis include, but are not limited to, upper gastrointestinal(GI) endoscopy, upper GI series, ultrasound tests, gastric emptyingscintigraphy, gastric emptying breath test, antral manometry,electrogastrography, and/or electrogastroenterography.

Upper GI endoscopy can be used to rule out other conditions that couldresult in delayed gastric emptying (such as, e.g., a physicalobstruction). Upper GI endoscopy typically involves use of an endoscope(e.g., a small, flexible tube with a light) to visualize the upper GItract, including, e.g., the esophagus, stomach, and duodenum (the firstpart of the small intestine). The endoscope is generally used to imagethe stomach and/or duodenum. A small camera mounted on the endoscope cantransmit a video image to a monitor, allowing close examination of theintestinal lining. Upper GI endoscopy may show physical blockage of theupper GI tract, for example, a large bezoar (e.g., solid collections offood, mucus, vegetable fiber, hair, or other material). In someembodiments, the subject is diagnosed with gastroparesis if the subjectexhibits a symptom of gastroparesis and upper GI endoscopy does notreveal a physical blockage causing the delayed gastric emptying.

An upper GI series may be performed to look at the small intestine. Thetest may be performed at a hospital or outpatient center by an x-raytechnician, and the images may be interpreted by a radiologist. Duringthe procedure, the subject may stand or sit in front of an x-ray machineand drink barium, a chalky liquid. Barium may coat the small intestine,making signs of gastroparesis show up more clearly on x rays.Gastroparesis may be indicated in cases wherein the x-ray shows food inthe stomach after fasting. In some embodiments, the subject is diagnosedwith gastroparesis if an upper GI series reveals food in the stomachafter fasting.

Ultrasound can be useful in ruling out other syndromes which may sharesymptoms in common with gastroparesis. Such other syndromes includegallbladder disease and pancreatitis. Ultrasound generally uses adevice, called a transducer, that bounces safe, painless sound waves offorgans to create an image of their structure. The procedure can beperformed in a health care provider's office, outpatient center, orhospital by a specially trained technician. Ultrasound images may beinterpreted by a radiologist. The subject may be diagnosed withgastroparesis if the subject exhibits a symptom of gastroparesis andother syndromes such as, e.g., gallbladder disease, pancreatitis, areruled out by, for example, ultrasound.

Gastric emptying scintigraphy can be used to diagnose gastroparesis in asubject. Gastric emptying scintigraphy can involve ingestion of a blandmeal—such as eggs or an egg substitute—that contains a small amount ofradioactive material. The radioactive material may be 99-M Technetium(TC) sulfur colloid or other radioactive ligand. The test may beperformed in a radiology center or hospital. An external camera may beused to detect and/or measure radioactivity in the abdominal region.Radioactivity may be measured at timed intervals, e.g., at 1, 2, 3, and4 hours after the meal. Gastroparesis may be positively identified insubjects exhibiting more than 10 percent of the meal within the stomachat 4 hours. Other measures of gastric emptying include, but are notlimited to, the time at which 50% of the meal has been emptied out ofthe stomach. See, e.g., Thomforde, G. M. et al., Evaluation of aninexpensive screening scintigraphic test of gastric emptying, 36 J.Nucl. Med. 93 (1995), hereby incorporated by reference. In someembodiments, the subject is diagnosed with gastroparesis via gastricemptying scintigraphy.

A breath test useful for assessing gastric emptying can utilizeradioactively labeled food (e.g., labeled with C¹³-octanoic acid). C¹³from the food may be absorbed when it reaches the small bowel. Theabsorbed C¹³ can then be rapidly metabolized in the liver to produce¹³CO₂. The produced ¹³CO₂ may then be detected in the breath of thesubject. The subject's breath may be collected and sampled at definedintervals. The samples may be analyzed for ¹³CO₂ by any means known inthe art. The rate of appearance of ¹³CO₂ in the breath can be used toindicate the rate of gastric emptying. An exemplary method of performinga C¹³-octanoic acid breath test is described in Ghoos, Y. S., et al.,104 Gastroenterology 1640-1647 (1993), hereby incorporated by reference.In some embodiments, the subject is diagnosed with gastroparesis via abreath test.

Manometry generally refers to the assessment of pressure changes in alumen. Antral manometry, which can also be referred to as antro-duodenalmanometry, generally refers to techniques for the evaluation ofcontractile activity in the distal stomach and duodenum. Intraluminalpressure of the stomach and/or duodenum can be measured through pressuresensors which are introduced into the lumen via a catheter. Measurementsmay be recorded over time in order to assess intraluminal pressurechanges. Recordings may last for any amount of time. Intraluminalpressure changes can be used to indicate contractile patterns in thestomach and/or duodenum. Intraluminal pressure changes may be measuredin a fasting state and/or after ingestion of a meal (post-prandially).Post-prandial contractile hypomotility can be indicative ofgastroparesis in a subject. Accordingly, a subject may exhibitpost-prandial gastric hypomotility, as determined by manometry.

Electrogastrography generally refers to techniques and methods forrecording electrical activity of the stomach. Likewise,electrogastroenterography refers to techniques and methods for recordingelectrical activity of the stomach and small intestine. Such electricalactivity can be recorded from the gastrointestinal mucosa, serosa, orthe outer skin surface (cutaneously). Gastrointestinal mucosa can referto the mucous membrane layer of the GI tract. Gastrointestinal serosacan comprise a thin layer of cells which secrete serous fluid, and athin epithelial layer. Recordings can be made during a fasting state,and after ingestion of a meal (usually 60 minutes). Deviations from thenormal frequency of electrical activity can include bradygastria and/ortachygastria. Control subjects typically exhibit an increase inelectrical activity after a meal, indicative of increased GI motility.Subjects with aberrant GI motility can exhibit abnormal rhythms inactivity and/or impairments in the postprandial increase. A normalfrequency of GI electrical activity can be, e.g., 3 cycles per minute.Bradygastria, which can be characterized as a frequency of GI electricalactivity that is decreased from normal, e.g., that is less than 2 cyclesper minute for at least one minute, can be indicative of gastroparesis.In some embodiments, a subject may exhibit bradygastria.Electrogastrography (EGG) which measures electrical activity withcutaneous electrodes similar to those used in electrocardiograms canalso be used to diagnose gastroparesis. (Stern, R. N. et al. EGG. Commonissues in validation and methodology, 24 Psychophysiology 55-64 (1987)),hereby incorporated by reference. Accordingly, a subject may bediagnosed with gastroparesis as determined by electrogastrography.

The subject may be suffering from, may be diagnosed with, may beexhibiting a symptom of, or may be suspected of having gastroesophagealreflux disease (GERD). GERD can be a chronic condition resulting ingastroesophageal reflux. Symptoms of GERD include, e.g., heartburn, dry,chronic cough, wheezing, asthma, recurrent pneumonia, nausea, vomiting,sore throat, difficulty swallowing, pain in the chest or upper abdomen,dental erosion, bad breath, spitting up. GERD may be diagnosed with theaid of tests. Tests that are useful in the diagnosis of GERD include,e.g., upper GI series, described herein, upper endoscopy, esophageal pHmonitoring, and esophageal manometry.

The subject may be suffering from, may be diagnosed with, may beexhibiting a symptom of, or may be suspected of having enteric nervoussystem disorder which is associated with a vestibular disorder of theear. The vestibular disorder of the ear can be Menetrier's disease.Ménétrier's disease can be characterized by enlargement of ridges (alsoreferred to herein as rugae) along the inside of the stomach wall,forming giant folds in the lining of the stomach. Ménétrier disease mayalso cause a decrease in stomach acid resulting from a reduction inacid-producing parietal cells. Symptoms of Ménétrier disease include, byway of example only, severe stomach pain, nausea, frequent vomiting, andthe like.

The subject may be suffering from, may be diagnosed with, may beexhibiting a symptom of, or may be suspected of having cyclical vomitingsyndrome (CVS). Cyclical vomiting syndrome can be characterized byepisodes or cycles of severe nausea and vomiting that alternate withsymptom-free intervals. Such episodes can last for hours, or even days.Episodes can start at the same time of day, can last the same length oftime, and can occur with the same symptoms and level of intensity.Episodes can be so severe that a person has to stay in bed for days,unable to go to school or work. Other symptoms of cyclical vomitingsyndrome include, e.g., abdominal pain, diarrhea, fever, dizziness, andsensitivity to light during vomiting episodes. Continued vomiting maycause severe dehydration that can be life threatening. Symptoms ofdehydration include thirst, decreased. Cyclical vomiting syndrome may bediagnosed in a subject who has experienced the following symptoms for atleast 3 months: vomiting episodes that start with severevomiting—several times per hour—and last less than 1 week, three or moreseparate episodes of vomiting in the past year, and absence of nausea orvomiting between episodes.

The subject may be suffering from, may be diagnosed with, may beexhibiting a symptom of, or may be suspected of having Irritable BowelSyndrome (IBS). IBS generally refers to a syndrome in which subjectsexperience recurrent or chronic gastrointestinal symptoms. Symptoms ofIBS can include, e.g., abdominal pain, abdominal discomfort,constipation, diarrhea, mucus in the stool, abdominal bloating, or acombination of any of the above. IBS may be diagnosed when a person hashad abdominal pain or discomfort at least three times a month for thelast 3 months without other disease or injury that could explain thepain. The pain or discomfort of IBS may occur with a change in stoolfrequency or consistency or be relieved by a bowel movement. IBS can beclassified into four subtypes based on a subject's usual stoolconsistency. The four subtypes of IBS are: IBS with constipation(IBS-C), IBS with diarrhea (IBS-D), mixed IBS (IBS-M), and unsubtypedIBS (IBS-U). A subject with IBS-C may have hard or lumpy stools at least25 percent of the time, may have loose or watery stools less than 25percent of the time, or a combination of the two. A subject with IBS-Dmay have loose or watery stools at least 25 percent of the time, hard orlumpy stools less than 25 percent of the time, or a combination of thetwo. A subject with IBS-M may have hard or lumpy stools at least 25percent of the time and loose or watery stools at least 25 percent ofthe time. A subject with IBS-U may have hard or lumpy stools less than25 percent of the time, loose or watery stools less than 25 percent ofthe time, or a combination of the two. Constipation associated with IBSmay be due to slow or delayed gastric motility. In some embodiments, thesubject with IBS has experienced constipation. IBS can be diagnosed in asubject by any means known in the art or otherwise described herein. Forinstance, IBS may be diagnosed by a health care provider. The healthcare provider may conduct a physical exam and may take a medical historyof the subject. IBS may be diagnosed if a subject has exhibited one ormore symptoms of IBS for at least 3, 4, 5, or 6 months, with one or moresymptoms occurring at least three times a month for the previous 3months. Additional tests that may be useful in the diagnosis of IBSinclude, but are not limited to: a stool test, lower GI series, flexiblesigmoidoscopy, or colonoscopy.

The subject may be suffering from, may be diagnosed with, may beexhibiting a symptom of, or may be suspected of having functionaldyspepsia (e.g., impaired digestion). Symptoms of dyspepsia include butare not limited to, e.g., chronic or recurrent pain in the upperabdomen, upper abdominal fullness, postprandial fullness, early satiety,bloating, belching, nausea, vomiting, heartburn, sour taste in themouth. Functional dyspepsia (e.g., nonulcer dyspepsia) generally refersto dyspepsia without evidence of an organic disease that is likely toexplain the symptoms of dyspepsia. An example of functional dyspepsia isdyspepsia in the absence of an ulcer. Functional dyspepsia is estimatedto affect about 15% of the general population in western countries.Other exemplary ENS disorders include but are not limited to, e.g.,intestinal dysmotility, ganglioneruoma, multiple endocrine neoplasiatype 2B (MEN2B), gastrointestinal neuropathy, and intestinal neuronaldysplasia.

The subject may be suffering from, may be diagnosed with, may beexhibiting a symptom of, or may be suspected of having an entericnervous system disorder caused by another underlying disease. Forexample, the enteric nervous system disorder can be a Parkinson'sdisease-induced ENS disorder. Parkinson's disease-induced ENS disordercan be related to degeneration of dopamine ENS neurons. Symptoms of aParkinson's disease-induced ENS disorder include, e.g., constipation,nausea, vomiting, and the like. In some embodiments, a subject to betreated according to a method of the application is diagnosed with,suffering a symptom of, is suspected of having, Parkinson's disease, andfurther exhibits a symptom of an ENS disorder as described herein.

The subject may be suffering from, may be diagnosed with, may beexhibiting a symptom of, or may be suspected of having an entericnervous system disorder can associated with scleroderma. Scleroderma canbe characterized by hardening and tightening of the skin and connectivetissues. In some embodiments, the subject is suffering from, may bediagnosed with, may be exhibiting a symptom of, or may be suspected ofhaving gastroparesis associated with Scleroderma

The subject may be suffering from, may be diagnosed with, may beexhibiting a symptom of, or may be suspected of having adiabetes-associated enteric nervous system disorder. Thediabetes-associated enteric nervous system disorder can be adiabetes-associated gastroparesis. The subject may be suffering from,may be diagnosed with, may be exhibiting a symptom of, or may besuspected of having an enteric nervous system disorder associated withmultiple sclerosis.

Other diseases and clinical conditions that can cause an enteric nervoussystem disorder such as gastroparesis include, e.g., cancer,hypothyroidism, hyperthyroidism, hyperparathyroidism, adrenalinsufficiency (Addison's disease), gastric ulcer, gastritis,post-gastric surgery, such as, e.g., vagotomy (resection of the vagusnerve), antrectomy (resection of a portion of the stomach distal to theantrum of the stomach), subtotal gastrectomy (resection of a gastrictumor), gastrojejunostomy (a surgical procedure that connects two lumensof the GI tract, such as a proximal segment of stomach and a segment ofthe small intestine), fundoplication (a surgical procedure that wraps anupper portion of the stomach around a lower end of the esophagus),polymyositis (a persistent inflammatory muscle disease that can causemuscle weakness), muscular dystrophy (a disease that can causeprogressive muscle weakness), amyloidosis (characterized by buildup ofamyloid in a tissue or organ of the subject, such as in thegastrointestinal tract), intestinal pseudo-obstruction (a condition thatcauses symptoms that are associated with bowel obstruction but whereinno bowel obstruction is found), dermatomyositis (a disease characterizedby muscular inflammation), systemic lupus erythematosus (a systemicautoimmune disease that can affect various tissues of the body,including the nervous system), eating disorders such as, e.g., anorexiaand bulimia, depression, paraneoplastic syndrome, and high cervical cordlesions (e.g., lesions at spinal cord C4 or above).

The subject can be suffering a symptom of an enteric nervous systemdisorder. Exemplary symptoms are described herein. In some embodiments,the symptom is nausea and/or vomiting. In some embodiments, the cause ofthe symptom is unknown (e.g., unexplained nausea). In some embodiments,the symptom is a chronic or recurrent symptom. The subject may, forexample, experience the symptom for at least 3 days, at least 5 days, atleast 1 week, at least 2 weeks, at least 4 weeks, at least 1 month, atleast 2 months, at least 3 months, at least 4 months, at least 5 months,at least 6 months, at least 7 months, at least 8 months, at least 9months, at least 10 months, at least 11 months, at least 12 months (1year), at least 1.5 years, at least 2 years, at least 3 years, at least4 years, at least 5 years, at least 6 years, at least 7 years, at least8 years, at least 9 years, or at least 10 years. The subject mayexperience the symptom 1, 2, 3, 4, 5, 6, 7, 8, 8, 10, 11, 12, 13, 14,15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, ormore than 31 times a month.

The subject may be, e.g., a mouse, a rat, a hamster, a gerbil, a dog, acat, a primates such as, e.g., a monkey or human. In some embodiments,the subject is a human. The subject may be an adult, a child, or aninfant. The subject can be of any age.

Use of the Pharmaceutical Compositions

Pharmaceutical compositions as described herein can be safelyadministered to a subject. Pharmaceutical compositions as describedherein can be administered without necessarily increasing risk ofdeveloping a deleterious cardiac side effect. For example,pharmaceutical compositions described herein may not increase risk ofmodulating cardiac action potential, and/or may not increase risk ofinducing long QT syndrome, and/or may not increase risk of cardiacarrest, and/or may not increases risk of sudden death by cardiac arrest.

The subject may be safely administered an effective amount of apharmaceutical composition as described herein for an unlimited amountof time. The subject may be safely administered an effective amount ofthe pharmaceutical composition acutely or chronically. For example, thesubject may be safely administered an effective amount of thepharmaceutical composition once, for one day, for at least 2 days, forat least 3 days, for at least four days, for five days, for at leastfive days, for at least six days, for at least seven days (1 week), forat least 2 weeks, for at least 3 weeks, for at least 4 weeks, for atleast 5 weeks, for at least 6 weeks, for at least 7 weeks, for at least8 weeks, for at least 9 weeks, for at least 10 weeks, for at least 11weeks, for at least 12 weeks, for at least 3 months, for at least 4months, for at least 5 months, for at least 6 months, for at least 7months, for at least 8 months, for at least 9 months, for at least 10months, for at least 11 months, for at least 12 months (1 year), for atleast 2 years, for at least 5 years, or for at least a decade.

Administration of a pharmaceutical composition as described herein mayconfer an acceptable risk that the subject will develop an unwantedcardiac side effect. Risk of pharmaceutical composition administrationon developing such unwanted cardiac side effect can be determined by anymeans known in the art, or as described herein. For example, risk can bedetermined by comparing the incidence of sudden death in a population ofsubjects administered the pharmaceutical composition as compared toincidence of sudden death in a population of control subjects that havenot been administered the pharmaceutical composition. Risk can bedetermined by tracking the number of subjects administered thepharmaceutical composition who experienced the unwanted cardiac sideeffect, and the number of subjects administered the pharmaceuticalcomposition who did not experience the unwanted cardiac side effect. Forexample, if a=the number of subjects administered the pharmaceuticalcomposition who experienced the unwanted cardiac side effect, and b=thenumber of subjects administered the pharmaceutical composition who didnot experience the unwanted cardiac side effect, the risk ofexperiencing the unwanted cardiac side effect conferred by beingadministered the pharmaceutical composition can be calculated asa/(a+b). Relative risk (RR) may be used to compare the risk ofdeveloping an unwanted cardiac side effect conferred by administrationof the pharmaceutical composition to the risk of developing the unwantedcardiac side effect in a population of subjects that have not beenadministered the pharmaceutical composition. For example, if a=thenumber of subjects administered the pharmaceutical composition whoexperienced the unwanted cardiac side effect, b=the number of subjectsadministered the pharmaceutical composition who did not experience theunwanted cardiac side effect, c=the number of subjects not administeredthe pharmaceutical composition who experienced the unwanted cardiac sideeffect, and d=the number of subjects not administered the pharmaceuticalcomposition who did not experience the unwanted cardiac side effect, RRconferred by administration of the pharmaceutical composition can becalculated as a/(a+b)/(c/(c+d). For other example, risk can bedetermined by calculating an odds ratio.

The RR of administration of a pharmaceutical composition as describedherein with sudden cardiac death can be less than 3.8, less than 3.7,less than 3.6, less than 3.5, less than 3.4, less than 3.3, less than3.2, less than 3.1, less than 3.0, less than 2.9, less than 2.8, lessthan 2.7, less than 2.6, less than 2.5, less than 2.4, less than 2.3,less than 2.2, less than 2.1, less than 2.0, less than 1.9, less than1.8, less than 1.7, less than 1.6, less than 1.5, less than 1.4, lessthan 1.3, less than 1.2, less than 1.1, less than 1.05, about 1, or lessthan 1.

The odds ratio of administration of a pharmaceutical compositiondescribed herein with sudden cardiac death can be an acceptable oddsratio. The term odds ratio (OR) generally refers to a measure ofassociation between an exposure (e.g., exposure to a drug) and anoutcome (e.g., sudden cardiac death). The OR can represent the odds thatthe outcome will occur given a particular exposure, as compared to theodds of the outcome occurring in the absence of that exposure. Oddsratios can be used in case-control studies, as well as incross-sectional and cohort study design studies. For example, if a=thenumber of subjects administered the pharmaceutical composition whoexperienced the unwanted cardiac side effect, b=the number of subjectsadministered the pharmaceutical composition who did not experience theunwanted cardiac side effect, c=the number of subjects not administeredthe pharmaceutical composition who experienced the unwanted cardiac sideeffect, and d=the number of subjects not administered the pharmaceuticalcomposition who did not experience the unwanted cardiac side effect, ORconferred by administration of the pharmaceutical composition can becalculated as ad/bc.

The OR of administration of a pharmaceutical composition describedherein with sudden cardiac death can be less than 3.8, less than 3.7,less than 3.6, less than 3.5, less than 3.4, less than 3.3, less than3.2, less than 3.1, less than 3.0, less than 2.9, less than 2.8, lessthan 2.7, less than 2.6, less than 2.5, less than 2.4, less than 2.3,less than 2.2, less than 2.1, less than 2.0, less than 1.9, less than1.8, less than 1.7, less than 1.6, less than 1.5, less than 1.4, lessthan 1.3, less than 1.2, less than 1.1, less than 1.05, about 1, or lessthan 1.

Unlike other dopamine modulating drugs previously indicated for thetreatment of ENS, the pharmaceutical compositions described herein foruse in the treatment of ENS are peripherally restricted. Accordingly,such pharmaceutical compositions can be safely administered to a subjectwithout increasing risk in the subject for developing motor-relateddysfunction mediated by brain dopaminergic signaling. For example, suchpharmaceutical compositions can be safely administered to a subjectwithout increasing risk in the subject for developing an extrapyramidalside effect. Exemplary extrapyramidal side effects include, e.g.,tardive dyskinesia (involuntary asymmetrical movements of the muscles),dystonia (characterized by sustained muscle contractions), akinesia(lack of movement), akathisia (feeling of motor restlessness),bradykinesia (slowed movements), stiffness, and tremor, twisting and/orrepetitive movements, abnormal postures, muscle spasms, e.g., musclespasms of the neck (torticullis), muscle spasms of the eyes (oculogyriccrisis) tongue spasms, spasms of the jaw, and the like. Extrapyramidalsymptoms can be assessed by any means known in the art or otherwisedescribed herein. For example, extrapyramidal symptoms may be assessedusing the Simpson-Angus Scale (SAS) and/or the Barnes Akathisia RatingScale (BARS). In some embodiments the odds ratio of administration ofthe pharmaceutical compositions described herein for use in treating anenteric nervous system disorder with incidence of an extrapyramidal sideeffect is less than 4, less than 3.9, less than 3.8, less than 3.7, lessthan 3.6, less than 3.5, less than 3.4, less than 3.3, less than 3.2,less than 3.1, less than 3.0, less than 2.9, less than 2.8, less than2.7, less than 2.6, less than 2.5, less than 2.4, less than 2.3, lessthan 2.2, less than 2.1, less than 2.0, less than 1.9, less than 1.8,less than 1.7, less than 1.6, less than 1.5, less than 1.4, less than1.3, less than 1.2, less than 1.1, less than 1.05, about 1, or less than1.

The pharmaceutical compositions of the application can promote gastricmotility upon administration to the subject. Such pharmaceuticalcompositions may promote gastric motility by, for example, reducingdopamine D2-receptor mediated signaling in an enteric neuron of thesubject. For example, the pharmaceutical compositions can antagonizedopamine D2 receptors in an enteric neuron of the subject. For otherexample, the pharmaceutical compositions may reduce the dopaminergicneurotransmission of an enteric neuron.

Gastric motility can be assessed by any means known to those of skill inthe art or otherwise described herein. For example, gastric motility canbe assessed by antral manometry, or by methods useful in the diagnosisof gastroparesis. Exemplary methods useful in the diagnosis ofgastroparesis are described herein.

Administration of the pharmaceutical compositions as described hereincan improve gastric motility as compared to a control subject and/orcontrol population. The control subject can be an individual that hasnot been administered a pharmaceutical composition described herein. Acontrol population can be a plurality of individuals that have not beenadministered a pharmaceutical composition described herein. The controlsubject can be a subject that is suffering from, that has been diagnosedwith, be suspected of having, or exhibiting a symptom of an ENSdisorder, that is not administered a pharmaceutical composition asdescribed herein. The control subject does not necessarily need to be adifferent individual, but may be the same subject at a time point priorto receiving a dose of a pharmaceutical composition as described herein.The control subject may be the same subject at a time point subsequentto receiving a dose of a pharmaceutical composition as described herein,after a sufficient time has passed such that the pharmaceuticalcomposition is no longer acting in the subject. The control subject canbe a different subject. In some embodiments, administration of a thepharmaceutical composition increases gastric motility by at least 25%,30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%,100%, or over 100% as compared to a control subject.

In some embodiments, administration of a pharmaceutical compositiondescribed herein is effective in treating a symptom of an entericnervous system disorder in the subject. Exemplary symptoms are describedherein. The symptom may be selected from the group consisting of nausea,vomiting, delayed gastric emptying, diarrhea, abdominal pain, gas,bloating, gastroesophageal reflux, reduced appetite, weight loss, andconstipation. In particular cases, administration of a pharmaceuticalcomposition described herein reduces nausea in the subject.Administration of a pharmaceutical composition as described herein mayreduce severity of any of the symptoms described herein. In some cases,administration of a pharmaceutical composition as described hereinreduces symptom severity by 1-5%, 2-10%, 5-20%, 10-30%, 20-50%, 40-70%,50-80%, 70-90%, 80-95%, 90-100%. In some cases, administration of apharmaceutical composition as described herein reduces symptom severityby at least 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 15%, 20%, 25%, 30%,35%, 40%, 45%, 50%, 60%, 70%, 80%, 90%, or more than 90%.

Administration of a pharmaceutical composition as described herein mayreduce frequency of onset of a symptom. In some cases, administration ofa pharmaceutical composition as described herein reduces frequency ofsymptom onset by 1-5%, 2-10%, 5-20%, 10-30%, 20-50%, 40-70%, 50-80%,70-90%, 80%, 70-90%, 80-95%, 90-100%. In some cases, administration of apharmaceutical composition as described herein reduces frequency ofsymptom onset by at least 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 15%,20%, 25%, 30%, 35%, 40%, 45%, 50%, 60%, 70%, 80%, 90%, or more than 90%.In some cases, administration of a pharmaceutical composition asdescribed herein reduces frequency of symptom onset to less than 1episode a day, less than 1 episode a week, less than 2 episodes a month,less than 1 episode a month, less than 1 episode every 2 months, lessthan 1 episode every 3 months, less than 1 episode every 4 months, lessthan 1 episode every 5 months, less than 1 episode every 6 months, lessthan 1 episode every 7 months, less than 1 episode every 8 months, lessthan 1 episode every 9 months, less than 1 episode every 10 months, lessthan 1 episode every 11 months, or less than 1 episode every 12 months(1 year).

hERG channel inhibition can be determined by any means known in the artor otherwise described herein. hERG channel inhibition can be assessedin vitro, for example, by utilizing hERG expressing cultured cells.hERG-expressing cultured cells for the purposes of assessing hERGchannel inhibition are available from a number of commercial vendors,such as, e.g., Life Technologies, Cyprotex, and the like. hERG channelinhibition can be assessed by a variety of means known in the art,including, e.g., voltage clamp studies, hERG binding assays, and thelike. Voltage clamp studies can employ the use of commercially availablehigh throughput systems. Exemplary high-throughput systems are describedin, e.g., U.S. Pat. No. 8,329,009, and US Patent Application Pub. No.20020164777, which are hereby incorporated by reference. hERG bindingassays can include competition and/or saturation binding assays using^(3H)dofetilide. Such assays are described in J Pharmacol ToxicolMethods. 2004 November-December; 50(3):187-99, which is herebyincorporated by reference. hERG channel inhibition can be determined byin vivo studies, for example, by assessment of cardiac action potentialsin large animal models, e.g., canines.

Minimal hERG inhibition can be evidenced by an IC₅₀ that is higher than0.1 μM, higher than 0.2 μM, higher than 0.3 μM, higher than 0.4 μM,higher than 0.5 μM, higher than 0.6 μM, higher than 0.7 μM, higher than0.8 μM, higher than 0.9 μM, higher than 1 μM, higher than 2 μM, higherthan 3 μM, higher than 4 μM, higher than 5 μM, higher than 6 μM, higherthan 7 μM, higher than 8 μM, higher than 9 μM, higher than 10 μM, higherthan 15 μM, higher than 20 μM, higher than 30 μM, higher than 40 μM,higher than 50 μM, higher than 60 μM, higher than 70 μM, higher than 80μM, higher than 90 μM, or higher than 100 μM.

Minimal hERG inhibition can also be evidenced by measuring, at any givendose of a drug, the % inhibition of hERG-mediated tail current.hERG-mediated tail current can be measured by voltage clamp studies,e.g., by patch clamps studies. For example, hERG-mediated tail currentcan be measured in an hERG-expressing cell prior to contact of the cellwith a test agent. hERG-mediated tail current can then be measured inthe hERG-expressing cell after contact with a dose of the test agent.The differences between the hERG-mediated tail current before and afteradministration of the test agent can be used to determine the extent towhich the test agent inhibited hERG-mediated tail current. A suitableagent for use in the disclosed methods can, at a 1 μM dose, inhibithERG-mediated tail current by less than 50%, less than 45%, less than40%, less than 35%, less than 30%, less than 25%, less than 20%, lessthan 15%, less than 10%, less than 9%, less than 8%, less than 7%, lessthan 6%, less than 5%, less than 4%, less than 3%, less than 2%, lessthan 1%, less than 0.5%, less than 0.4%, less than 0.3%, less than0.25%, less than 0.2%, less than 0.15%, or less than 0.1%. A suitableagent for use in the disclosed methods can, at a 100 nM dose, inhibithERG-mediated tail current by less than 20%, less than 15%, less than10%, less than 9%, less than 8%, less than 7%, less than 6%, less than5%, less than 4%, less than 3%, less than 2%, less than 1%, less than0.5%, less than 0.4%, less than 0.3%, less than 0.25%, less than 0.2%,less than 0.15%, or less than 0.1%. In some embodiments, metopimazinecan, at a 3 μM dose, inhibit hERG-mediated tail current by less than50%, less than 45%, less than 40%, less than 35%, less than 30%, lessthan 25%, less than 20%, less than 15%, less than 10%, less than 9%,less than 8%, less than 7%, less than 6%, less than 5%, less than 4%,less than 3%, less than 2%, less than 1%, less than 0.5%, less than0.4%, less than 0.3%, less than 0.25%, less than 0.2%, less than 0.15%,or less than 0.1%. In some embodiments, metopimazine acid can, at a 10μM dose or higher, inhibit hERG-mediated tail current by less than 50%,less than 45%, less than 40%, less than 35%, less than 30%, less than25%, less than 20%, less than 15%, less than 10%, less than 9%, lessthan 8%, less than 7%, less than 6%, less than 5%, less than 4%, lessthan 3%, less than 2%, less than 1%, less than 0.5%, less than 0.4%,less than 0.3%, less than 0.25%, less than 0.2%, less than 0.15%, orless than 0.1%.

Exemplary Pharmaceutical Compositions

Pharmaceutical compositions utilized in the methods of the applicationmay include a pharmaceutically acceptable carrier. The pharmaceuticallyacceptable carrier for the present compositions may include, but are notlimited to, amino acids, peptides, biological polymers, non-biologicalpolymers, simple sugars or starches, inorganic salts, and gums, whichmay be present singly or in combinations thereof. The peptides used inthe acceptable carrier may include, e.g., gelatin and/or albumin.Cellulose or its derivatives may be used in the pharmaceuticallyacceptable carrier. The sugar used in the acceptable carrier may belactose and/or glucose. Other useful sugars which may be utilized in thepharmaceutical compositions include but are not limited to, fructose,galactose, lacticol, maltitol, maltose, mannitol, melezitose,myoinositol, palatinate, raffinose, stachyose, sucrose, tehalose,xylitol, hydrates thereof, and combinations of thereof. Binders may beincluded in the pharmaceutically acceptable carrier. Examples of bindersinclude, but are not limited to, starches (for example, corn starch orpotato starch), gelatin; natural or synthetic gums such as acacia,sodium alginate, powdered tragacanth, guar gum, cellulose or cellulosederivatives (for example, methycellulose, ethyl cellulose, celluloseacetate); microcrystalline cellulose, polyvinyl pyrrolidone, andmixtures thereof. Inorganic salts used in the acceptable carrier may bea magnesium salt, for example, magnesium chloride or magnesium sulfate.Other inorganic salts may be used, for example, calcium salts. Examplesof calcium salts include, but are not limited to, calcium chloride,calcium sulfate. Other examples of substances which may be used in thepharmaceutically acceptable carrier include, but are not limited to,vegetable oils, such as peanut oil, cottonseed oil, olive oil, corn oil;polyols such as glycerin, propylene glycol, polyethylene glycol;pyrogen-free water, isotonic saline, phosphate buffer solutions;emulsifiers, such as the Tweens®; wetting agents, lubricants, coloringagents, flavoring agents, preservatives.

The term “wetting agents” may be used interchangeably with“surfactants”, and refers to substances that lower the surface tensionof a liquid, thus allowing the liquid to spread more easily. Surfactantwhich can be used to form pharmaceutical compositions and dosage formsof the application include, but are not limited to, hydrophilicsurfactants, lipophilic surfactants, and mixtures thereof. That is, amixture of hydrophilic surfactants may be employed, a mixture oflipophilic surfactants may be employed, or a mixture of at least onehydrophilic surfactant and at least one lipophilic surfactant may beemployed.

A suitable hydrophilic surfactant may generally have an HLB value of atleast 10, while suitable lipophilic surfactants may generally have anHLB value of or less than about 10. A useful parameter that may be usedto characterize the relative hydrophilicity and hydrophobicity of nonionic amphiphilic compounds is the hydrophilic-lipophilic balance (“HLB”value). Surfactants with lower HLB values are more hydrophobic, and havegreater solubility in oils, while surfactants with higher HLB values aremore hydrophilic, and have greater solubility in aqueous solutions.Hydrophilic surfactants are generally considered to be those compoundshaving an HLB value greater than about 10, as well as anionic, cationic,or zwitterionic compounds for which the HLB scale is not generallyapplicable. Similarly, lipophilic (i.e., hydrophobic) surfactants aregenerally considered to be compounds having an HLB value equal to orless than about 10. However, HLB value of a surfactant merely provides arough guide generally used to enable formulation of industrial,pharmaceutical and cosmetic emulsions.

Hydrophilic surfactants may be either ionic or non-ionic. Suitable ionicsurfactants include, but are not limited to, alkylammonium salts, fattyacid derivatives of amino acids, glyceride derivatives of amino acids,fusidic acid salts, oligopeptides, and polypeptides, oligopeptides, andpolypeptides, lecithins and hydrogenated lecithins, lysolecithins andhydrogenated lysolecithins, phospholipids and derivatives thereof, fattyacid salts, lysophospholipids and derivatives thereof, carnitine fattyacid ester salts, salts of alkylsulfates, sodium docusate,acylactylates, mono- and di-acetylated tartaric acid esters of mono- anddi-glycerides, succinylated mono- and di-glycerides, citric acid estersof mono- and di-glycerides, and mixtures thereof.

Within the aforementioned group, ionic surfactants include, but are notlimited to, lecithins, lysolecithin, phospholipids, lysophospholipidsand derivatives thereof, carnitine fatty acid ester salts, fatty acidsalts, salts of alkylsulfates, sodium docusate, acylactylates, mono- anddi-acetylated tartaric acid esters of mono- and di-glycerides,succinylated mono- and di-glycerides, citric acid esters of mono- anddi-glycerides, and mixtures thereof.

Ionic surfactants may be the ionized forms of lactylic esters of fattyacids, lecithin, lysolecithin, phosphatidylethanolamine,phosphatidylcholine, phosphatidylglycerol, phosphatidic acid,phosphatidylserine, lysophosphatidylcholine, lysophosphatidylserine,lysophosphatidylethanolamine, lysophosphatidylglycerol, lysophosphatidicacid, PEG-phosphatidylethanolamine, PVP-phosphatidylethanolamine,stearoyl-2-lactylate, stearoyl lactylate, succinylated monoglycerides,mono/diacetylated tartaric acid esters of mono/diglycerides, citric acidesters of mono/diglycerides, cholylsarcosine, caproate, caprylate,caprate, laurate, myristate, palmitate, oleate, linoleate, linolenate,stearate, ricinoleate, lauryl sulfate, teracecyl sulfate, docusate,lauroyl carnitines, palmitoyl carnitines, myristoyl carnitines, andsalts and mixtures thereof.

Hydrophilic non-ionic surfactants may include, but not limited to,alkylglucosides, alkylthioglucosides, alkylmaltosides, laurylmacrogolglycerides, polyoxyalkylene alkyl ethers such as polyethyleneglycol alkyl ethers, polyoxyalkylene alkylphenols such as polyethyleneglycol alkyl phenols, polyethylene glycol glycerol fatty acid esters,polyoxyalkylene alkyl phenol fatty acid esters such as polyethyleneglycol fatty acids monoesters and polyethylene glycol fatty acidsdiesters, polyglycerol fatty acid esters,polyoxyethylene-polyoxypropylene block copolymers and mixtures thereof,polyoxyalkylene sorbitan fatty acid esters such as polyethylene glycolsorbitan fatty acid esters, hydrophilic transesterification products ofa polyol with at least one member of the group consisting of glycerides,vegetable oils, hydrogenated vegetable oils, fatty acids, and sterols,polyoxyethylene sterols and derivatives or analogues thereof,polyoxyethylated vitamins and derivatives thereof, polyethylene glycolsorbitan fatty acid esters and hydrophilic transesterification productsof a polyol with at least one member of the group consisting oftriglycerides, vegetable oils, and hydrogenated vegetable oils. Thepolyol may be glycerol, ethylene glycol, polyethylene glycol, sorbitol,propylene glycol, pentaerythritol, or a saccharide.

Other hydrophilic-non-ionic surfactants include, without limitation,PEG-10 laurate, PEG-12 laurate, PEG-12 oleate, PEG-15 oleate, PEG-20oleate, PEG-20 laurate, PEG-32 dilaurate, PEG-32 laurate, PEG-20dioleate, PEG-32 oleate, PEG-200 oleate, PEG-400 oleate, PEG-15stearate, PEG-32 distearate, PEG-40 stearate, PEG-100 stearate, PEG-20dilaurate, PEG-25 glyceryl trioleate, PEG-32 dioleate, PEG-20 glyceryllaurate, PEG-20 trioleate, PEG-30 glyceryl laurate, PEG-20 glycerylstearate, PEG-20 glyceryl oleate, PEG-30 glyceryl oleate, PEG-30glyceryl laurate, PEG-40 glyceryl laurate, PEG-50 hydrogenated castoroil, PEG-40 castor oil, PEG-35 castor oil, PEG-60 castor oil, PEG-40palm kernel oil, PEG-40 hydrogenated castor oil, PEG-60 hydrogenatedcastor oil, PEG-60 corn oil, PEG-6 caprate/caprylate glycerides, PEG-8caprate/caprylate glycerides, polyglyceryl-10 laurate, PEG-30cholesterol, PEG-25 phytosterol, PEG-30 soya sterol, PEG-40 sorbitanoleate, PEG-80 sorbitan laurate, polysorbate 20, polysorbate 80, POE-9lauryl ether, POE-23 lauryl ether, POE-10 oleyl ether, POE-20 oleylether, POE-20 stearyl ether, tocopheryl PEG-100 succinate, PEG-24cholesterol, polyglyceryl-10oleate, Tween 40, Tween 60, sucrosemonostearate, sucrose monolaurate, sucrose monopalmitate, PEG 10-100nonyl phenol series, PEG 15-100 octyl phenol series, and poloxamers.

Suitable lipophilic surfactants include, but are not limited to, fattyalcohols, glycerol fatty acid esters, acetylated glycerol fatty acidesters, lower alcohol fatty acids esters, propylene glycol fatty acidesters, sorbitan fatty acid esters, polyethylene glycol sorbitan fattyacid esters, sterols and sterol derivatives, polyoxyethylated sterolsand sterol derivatives, polyethylene glycol alkyl ethers, sugar ethers,sugar esters, hydrophobic transesterification products of a polyol withat least one member of the group consisting of glycerides, vegetableoils, hydrogenated vegetable oils, fatty acids and sterols, oil-solublevitamins/vitamin derivatives, lactic acid derivatives of mono- anddi-glycerides, and mixtures thereof. Within this group, preferredlipophilic surfactants include glycerol fatty acid esters, propyleneglycol fatty acid esters, and mixtures thereof, or are hydrophobictransesterification products of a polyol with at least one member of thegroup consisting of vegetable oils, hydrogenated vegetable oils, andtriglycerides.

Lubricants that may be used in the pharmaceutical composition include,but are not limited to, agar, calcium stearate, magnesium stearate,mineral oil, light mineral oil, glycerin, sorbitol, mannitol,polyethylene glycol, other glycols, stearic acid, sodium lauryl sulfate,talc, hydrogenated vegetable oil (e.g., peanut oil, cottonseed oil,sunflower oil, sesame oil, olive oil, corn oil, and soybean oil), zincstearate, ethyl oleate, ethylaureate, or mixtures thereof. Additionallubricants include, by way of example, a syloid silica gel, a coagulatedaerosol of synthetic silica, or mixtures thereof. A lubricant canoptionally be added, in an amount of less than about 1 weight percent ofthe pharmaceutical composition.

The composition may include one or more pharmaceutically acceptableadditives, which may include, but are not limited to, detackifiers,anti-foaming agents, buffering agents, antioxidants, polymers,preservatives, chelating agents, odorants, opacifiers, suspendingagents, fillers, plasticizers, and mixtures thereof.

In some embodiments, the pharmaceutically acceptable carrier comprisesmore than 90%, more than 80%, more than 70%, more than 60%, more than50%, more than 40%, more than 30%, more than 20%, more than 10%, morethan 9%, more than 8%, more than 6%, more than 5%, more than 4%, morethan 3%, more than 2%, more than 1%, more than 0.5%, more than 0.4%,more than 0.3%, more than 0.2%, more than 0.1%, more than 0.09%, morethan 0.08%, more than 0.07%, more than 0.06%, more than 0.05%, more than0.04%, more than 0.03%, more than 0.02%, more than 0.01%, more than0.009%, more than 0.008%, more than 0.007%, more than 0.006%, more than0.005%, more than 0.004%, more than 0.003%, more than 0.002%, more than0.001%, more than 0.0009%, more than 0.0008%, more than 0.0007%, morethan 0.0006%, more than 0.0005%, more than 0.0004%, more than 0.0003%,more than 0.0002%, or more than 0.0001% of the pharmaceuticalcomposition by w/w, w/v or v/v.

In some embodiments, the concentration of the crystalline form ofmetopimazine mesylate (e.g., metopimazine mesylate Crystal Form A ormetopimazine mesylate Crystal Form B) in the composition comprises lessthan 100%, less than 90%, less than 80%, less than 70%, less than 60%,less than 50%, less than 40%, less than 30%, less than 20%, less than10%, less than 9%, less than 8%, less than 6%, less than 5%, less than4%, less than 3%, less than 2%, less than 1%, less than 0.5%, less than0.4%, less than 0.3%, less than 0.2%, less than 0.1%, less than 0.09%,less than 0.08%, less than 0.07%, less than 0.06%, less than 0.05%, lessthan 0.04%, less than 0.03%, less than 0.02%, less than 0.01%, less than0.009%, less than 0.008%, less than 0.007%, less than 0.006%, less than0.005%, less than 0.004%, less than 0.003%, less than 0.002%, less than0.001%, less than 0.0009%, less than 0.0008%, less than 0.0007%, lessthan 0.0006%, less than 0.0005%, less than 0.0004%, less than 0.0003%,less than 0.0002%, or less than 0.0001% of the pharmaceuticalcomposition by w/w, w/v or v/v.

In some embodiments, the concentration of the crystalline form ofmetopimazine mesylate (e.g., metopimazine mesylate Crystal Form A ormetopimazine mesylate Crystal Form B) is in the range of about 0.0001%to about 50%, about 0.001% to about 40%, about 0.01% to about 20%, about0.02% to about 29%, about 0.03% to about 28%, about 0.04% to about 27%,about 0.05% to about 26%, about 0.06% to about 25%, about 0.07% to about24%, about 0.08% to about 23%, about 0.09% to about 22%, about 0.1% toabout 21%, about 0.2% to about 20%, about 0.3% to about 19%, about 0.4%to about 18%, about 0.5% to about 17%, about 0.6% to about 16%, about0.7% to about 15%, about 0.8% to about 14%, about 0.9% to about 12%,about 1% to about 10% of the pharmaceutical composition by w/w, w/v orv/v.

In some embodiments, the concentration of the crystalline form ofmetopimazine mesylate (e.g., metopimazine mesylate Crystal Form A ormetopimazine mesylate Crystal Form B) is in the range of about 0.0001%to about 5%, about 0.001% to about 4%, about 0.01% to about 2%, about0.02% to about 1%, or about 0.05% to about 0.5% of the pharmaceuticalcomposition by w/w, w/v or v/v.

Described below are some non-limiting examples of pharmaceuticalcompositions.

Pharmaceutical Compositions for Oral Administration

The pharmaceutical composition comprising an effective amount of acrystalline form of metopimazine mesylate (e.g., metopimazine mesylateCrystal Form A or metopimazine mesylate Crystal Form B) can beformulated for oral administration. In some embodiments, thepharmaceutical composition comprising an effective amount of acrystalline form of metopimazine mesylate (e.g., metopimazine mesylateCrystal Form A or metopimazine mesylate Crystal Form B) for oraladministration is a solid pharmaceutical composition. In someembodiments, the solid pharmaceutical composition may be presented asdiscrete (e.g., unit) oral dosage forms. Non-limiting examples ofdiscrete oral dosage forms include tablets, capsules, caplets, gelatincapsules, sustained release formulations, lozenges, thin films,lollipops, chewing gum. In some embodiments, the discrete oral dosageform is an orally disintegrating oral dosage form, such as, e.g., anorally disintegrating tablet.

Discrete oral dosage forms such as tablets may be coated by knowntechniques to delay or prolong absorption in the gastrointestinal tract,thus providing a sustained action of a longer period of time. In someembodiments, the crystalline form of metopimazine mesylate (e.g.,metopimazine mesylate Crystal Form A or metopimazine mesylate CrystalForm B) is mixed with one or more inert solid diluents, such as calciumcarbonate or calcium phosphate. In some embodiments, the crystallineform of metopimazine mesylate (e.g., metopimazine mesylate Crystal FormA or metopimazine mesylate Crystal Form B) is presented as soft gelatincapsules, wherein the crystalline form of metopimazine mesylate (e.g.,metopimazine mesylate Crystal Form A or metopimazine mesylate CrystalForm B) is mixed with water or an oil medium, such as peanut oil, orolive oil, for example.

In some embodiments, the pharmaceutical composition comprising aneffective amount of a crystalline form of metopimazine mesylate (e.g.,metopimazine mesylate Crystal Form A or metopimazine mesylate CrystalForm B) for oral administration is a liquid pharmaceutical composition.Non-limiting examples of liquid compositions for oral administrationinclude hydrophilic suspensions, emulsions, liquids, gels, syrups,slurries, solutions, elixirs, softgels, tinctures, and hydrogels. Insome embodiments, solid or liquid compositions comprising an effectiveamount of a crystalline form of metopimazine mesylate (e.g.,metopimazine mesylate Crystal Form A or metopimazine mesylate CrystalForm B) for oral administration comprise various sweetening or flavoringagents, or coloring agents. Examples of coloring agents include dyessuitable for food such as those known as F.D. & C. dyes and naturalcoloring agents such as grape skin extract, beet red powder, betacarotene, annato, carmine, turmeric, paprika, and so forth. Derivatives,analogues, and isomers of any of the above colored compound also may beused.

Such dosage forms may be prepared by methods well known to those skilledin the art, e.g., in a pharmacy. Such methods would comprise bringingthe crystalline form of metopimazine mesylate (e.g., metopimazinemesylate Crystal Form A or metopimazine mesylate Crystal Form B) intoassociation with the pharmaceutically acceptable carrier.

This application further encompasses anhydrous pharmaceuticalcompositions and dosage forms comprising an effective amount of acrystalline form of metopimazine mesylate (e.g., metopimazine mesylateCrystal Form A or metopimazine mesylate Crystal Form B), since water mayfacilitate the degradation of the crystalline form of metopimazinemesylate (e.g., metopimazine mesylate Crystal Form A or metopimazinemesylate Crystal Form B). In some embodiments, the anhydrouspharmaceutical compositions and dosage forms of the application areprepared using anhydrous or low moisture containing ingredients. In someembodiments, the anhydrous pharmaceutical compositions and dosage formsof the application are prepared under low humidity or low moistureconditions. The pharmaceutical compositions of the present applicationwhich contain lactose may be made anhydrous if substantial contact withmoisture and/or humidity during manufacturing, packaging, and/or storageis expected. An anhydrous pharmaceutical composition comprising aneffective amount of a crystalline form of metopimazine mesylate (e.g.,metopimazine mesylate Crystal Form A or metopimazine mesylate CrystalForm B) may be prepared and stored such that its anhydrous nature ismaintained. For example, the anhydrous compositions may be packagedusing materials known to prevent exposure to water such that they can beincluded in suitable formulary kits, examples of which include, but arenot limited to, hermetically sealed foils, plastic or the like, unitdose containers, blister packs, and strip packs.

Pharmaceutical Compositions for Injection or Parenteral Administration

In some embodiments, the pharmaceutical composition is formulated forparenteral administration. “Parenteral administration” generally refersto routes of administration other than the gastro-intestinal tract.Examples of parenteral administration include, but are not limited to,intravenous injection, intra-arterial injection, intrathecal injection(into the spinal cord), intratonsillary injection, subcutaneousinjection, intramuscular injection, infusion, or implantation. Infusionmay be intradermal, or subcutaneous, or through a transdermal implant.Exemplary pharmaceutical compositions for parenteral administration aredisclosed in the following references which are hereby incorporated byreference: U.S. Patent Application Pub. No 2006/0287221, U.S. Pat. Nos.5,244,925, 4,309,421, 4,158,707, and 5,164,405, all of which are herebyincorporated by reference.

Compositions formulated for parenteral administration may includeaqueous solutions and/or buffers commonly used for injection and/orinfusion. Commonly used aqueous buffers and/or solutions may include,but are not limited to sodium chloride solutions of about 0.9%,phosphate buffers, Lactated Ringer's solution, Acetated ringer'ssolution, phosphate buffered saline, citrate buffers, Tris buffers,histidine buffers, HEPES buffers, glycine buffers, N-glycylglycinebuffers, and the like. Other pharmaceutically acceptable carriers forparenteral administration may include ethanol, glycerol, propyleneglycol, cyclodextrin and cyclodextrin derivatives, vegetable oils, andthe like.

In some embodiments, pharmaceutical compositions for injection and/orinfusion contain preservatives present in amounts that effectivelyprevent or reduce microbial contamination or degradation. Variousagents, e.g., phenol, m-cresol, benzyl alcohol, parabens, chlorobutanol,methotrexate, sorbic acid, thimerosol, ethyl hydroxybenzoate, bismuthtribromophenate, methyl hydroxybenzoate, bacitracin, propylhydroxybenzoate, erythromycin, 5-fluorouracil, doxorubicin,mitoxantrone, rifamycin, chlorocresol, benzalkonium chlorides, may beused to prevent or reduce contamination.

In some embodiments, sterile solutions are prepared by incorporating acrystalline form of metopimazine mesylate (e.g., metopimazine mesylateCrystal Form A or metopimazine mesylate Crystal Form B) in the requiredamount in the appropriate solvent with various other ingredients asdescribed herein, as required, followed by filtered sterilization.Generally, dispersions are prepared by incorporating the varioussterilized active ingredients into a sterile vehicle which contains thebasic dispersion medium and the required other ingredients from thoseenumerated above. In the case of sterile powders for the preparation ofsterile injectable solutions, certain methods of preparation include butare not limited to vacuum-drying and freeze-drying techniques whichyield a powder of the active ingredient plus any additional desiredingredient from a previously sterile-filtered solution thereof.

In some embodiments, the pharmaceutical composition is formulated fortopical and/or transdermal delivery. Compositions of the presentapplication can be formulated into preparations in liquid, semi-solid,or solid forms suitable for local or topical administration. Examples offorms suitable for topical or local administration include but are notlimited to, gels, water soluble jellies, creams, lotions, suspensions,foams, powders, slurries, ointments, oils, pastes, suppositories,solutions, sprays, emulsions, saline solutions, dimethylsulfoxide(DMSO)-based solutions. In general, carriers with higher densities arecapable of providing an area with a prolonged exposure to the activeingredients. In contrast, a solution formulation may provide moreimmediate exposure of the active ingredient to the chosen area.

The pharmaceutical composition may comprise suitable solid or gel phasecarriers, which are compounds that allow increased penetration of, orassist in the delivery of, therapeutic molecules across the stratumcorneum barrier of the skin. There are many of thesepenetration-enhancing molecules known to those skilled in the art oftopical formulation. Examples of such carriers and excipients include,but are not limited to, alcohols (e.g., ethanol), fatty acids (e.g.,oleic acid), humectants (e.g., urea), glycols (e.g., propylene glycol),surfactants (e.g., isopropyl myristate and sodium lauryl sulfate),glycerol monolaurate, sulfoxides, pyrrolidones, terpenes (e.g.,menthol), amines, amides, alkanes, alkanols, water, calcium carbonate,calcium phosphate, various sugars, starches, cellulose derivatives,gelatin, and polymers such as polyethylene glycols.

Another exemplary formulation for use in the methods of the presentapplication employs transdermal delivery devices (“patches”). Suchtransdermal patches may be used to provide continuous or discontinuousinfusion of a crystalline form of metopimazine mesylate (e.g.,metopimazine mesylate Crystal Form A or metopimazine mesylate CrystalForm B) as described herein in controlled amounts, either with orwithout an additional agent. The construction and use of transdermalpatches for the delivery of pharmaceutical agents is well known in theart. See, e.g., U.S. Pat. Nos. 5,023,252; 4,992,445; and 5,001,139;which are herein incorporated by reference.

In some embodiments, the application provides a pharmaceuticalcomposition comprising an effective amount of a crystalline form ofmetopimazine mesylate (e.g., metopimazine mesylate Crystal Form A ormetopimazine mesylate Crystal Form B) as described herein fortransdermal delivery, and a pharmaceutical excipient suitable fordelivery by inhalation. Compositions for inhalation include solutionsand suspensions in pharmaceutically acceptable, aqueous or organicsolvents, or mixtures thereof, and powders. The liquid or solidcompositions may contain suitable pharmaceutically acceptable excipientsas described herein. The compositions may be administered by the oral ornasal respiratory route for systemic effect. In some embodiments,compositions in preferably pharmaceutically acceptable solvents may benebulized by use of inert gases. In some embodiments, nebulizedsolutions may be inhaled directly from the nebulizing device. In otherembodiments, nebulizing device may be attached to a face mask tent orintermittent positive pressure breathing machine. Solution, suspension,or powder compositions may be administered, preferably orally ornasally, from devices that deliver the formulation in an appropriatemanner.

Other Pharmaceutical Compositions

The pharmaceutical compositions employed in the present application maybe formulated for intraocular (ophthalmic), rectal, sublingual, buccal,or intranasal (e.g., intrapulmonary) administration. Formulationssuitable for intraocular administration include eye drops wherein theactive ingredient is dissolved or suspended in a suitable carrier,especially an aqueous solvent for the active ingredient. The activeingredient is preferably present in such formulations in a concentrationof 0.5 to 20%, advantageously 0.5 to 10% particularly about 1.5% w/w.Formulations suitable for sublingual administration, typically areformulated to dissolve rapidly upon placement in the mouth, allowing theactive ingredient to be absorbed via blood vessels under the tongue.Exemplary sublingual formulations include, e.g., lozenges comprising theactive ingredient in a flavored basis, usually sucrose and acacia ortragacanth; pastilles comprising the active ingredient in an inert basissuch as gelatin and glycerin, or sucrose and acacia; mouthwashescomprising the active ingredient in a suitable liquid carrier; orallydisintegrating tablets which may, for example, disintegrate in less than90 seconds upon placement in the mouth; and thin films. Suchdisintegration can be measured by an in vitro dissolution test.Formulations for buccal administration can include, e.g., buccaltablets, bioadhesive particles, wafers, lozenges, medicated chewinggums, adhesive gels, patches, films, which may be delivered as anaqueous solution, a paste, an ointment, or aerosol, to name a few.Formulations for rectal administration may be presented as a suppositorywith a suitable base comprising for example cocoa butter or asalicylate. Formulations suitable for intrapulmonary or nasaladministration can have a particle size for example in the range of 0.1to 500 microns (including particle sizes in a range between 0.1 and 500microns in increments microns such as 0.5, 1, 30 microns, 35 microns,etc.), which is administered by rapid inhalation through the nasalpassage or by inhalation through the mouth so as to reach the alveolarsacs. Suitable formulations include aqueous or oily solutions of theactive ingredient. Formulations suitable for aerosol or dry powderadministration may be prepared according to conventional methods and maybe delivered with other therapeutic agents such as compounds heretoforeused in the treatment or prophylaxis of cancerous infections asdescribed below. A pharmacological formulation of the presentapplication can be administered to the patient in an injectableformulation containing any compatible carrier, such as various vehicle,adjuvants, additives, and diluents; or the metopimazine mesylateutilized in the present application can be administered parenterally tothe patient in the form of slow-release subcutaneous implants ortargeted delivery systems such as monoclonal antibodies, vectoreddelivery, iontophoretic, polymer matrices, liposomes, and microspheres.Examples of delivery systems useful in the present application include:U.S. Pat. Nos. 5,225,182; 5,169,383; 5,167,616; 4,959,217; 4,925,678;4,487,603; 4,486,194; 4,447,233; 4,447,224; 4,439,196; and 4,475,196.Many other such implants, delivery systems, and modules are well knownto those skilled in the art.

Preparations for such pharmaceutical compositions are described in,e.g., Anderson, Philip O.; Knoben, James E.; Troutman, William G, eds.,Handbook of Clinical Drug Data, Tenth Edition, McGraw-Hill, 2002; Prattand Taylor, eds., Principles of Drug Action, Third Edition, ChurchillLivingston, N.Y., 1990; Katzung, ed., Basic and Clinical Pharmacology,Ninth Edition, McGraw Hill, 20037ybg; Goodman and Gilman, eds., ThePharmacological Basis of Therapeutics, Tenth Edition, McGraw Hill, 2001;Remingtons Pharmaceutical Sciences, 20th Ed., Lippincott Williams &Wilkins, 2000; Martindale, The Extra Pharmacopoeia, Thirty-SecondEdition (The Pharmaceutical Press, London, 1999); all of which areincorporated by reference herein in their entirety.

Exemplary Modes of Administration

Administration of a pharmaceutical composition as described herein canbe performed by any method that enables delivery of the crystalline formof metopimazine mesylate (e.g., metopimazine mesylate Crystal Form A ormetopimazine mesylate Crystal Form B) to the site of action. Thecomposition may be administered orally, parenterally, enterally,intraperitoneally, topically, transdermally, ophthalmically,intranasally, locally, non-orally, via spray, subcutaneously,intravenously, intratonsillary, intramuscularly, buccally, sublingually,rectally, infra-arterially, by infusion, or intrathecally. In someembodiments, the composition is administered orally. In some cases, theoral administration may comprise administration of any of the oraldosage forms as described herein. The effective amount of a crystallineform of metopimazine mesylate (e.g., metopimazine mesylate Crystal FormA or metopimazine mesylate Crystal Form B) administered will bedependent on the subject being treated, the severity of the disorder orcondition, the rate of administration, the disposition of thecrystalline form of metopimazine mesylate (e.g., metopimazine mesylateCrystal Form A or metopimazine mesylate Crystal Form B) and thediscretion of the prescribing physician.

A subject can be administered a daily dosage of a crystalline form ofmetopimazine mesylate (e.g., metopimazine mesylate Crystal Form A ormetopimazine mesylate Crystal Form B) as described herein for thetreatment of an enteric nervous system disorder. The daily dosage can befrom about 0.01 mg/kg to about 500 mg/kg of body weight per day.

In some embodiments, administration may comprise infusion. In somecases, infusion may involve chronic, steady dosing. Devices for chronic,steady dosing, e.g., by a controlled pump, are known in the art,(examples may be described in U.S. Pat. Nos. 7,341,577, 7,351,239,8,058,251, herein incorporated by reference).

Administration of the crystalline form of metopimazine mesylate (e.g.,metopimazine mesylate Crystal Form A or metopimazine mesylate CrystalForm B) may continue as long as necessary. In some embodiments, thecrystalline form of metopimazine mesylate (e.g., metopimazine mesylateCrystal Form A or metopimazine mesylate Crystal Form B) is administeredfor more than 1, 2, 3, 4, 5, 6, 7, 14, or 28 days. In particularembodiments, the crystalline form of metopimazine mesylate (e.g.,metopimazine mesylate Crystal Form A or metopimazine mesylate CrystalForm B) is administered for more than 5 days. In some embodiments, thecrystalline form of metopimazine mesylate (e.g., metopimazine mesylateCrystal Form A or metopimazine mesylate Crystal Form B) is administeredfor more than 12 weeks. In some embodiments, the crystalline form ofmetopimazine mesylate (e.g., metopimazine mesylate Crystal Form A ormetopimazine mesylate Crystal Form B) is administered for more than 1month, more than 2 months, more than 4 months, more than 6 months, morethan 1 year, more than 2 years, or more than 5 years. In someembodiments, the crystalline form of metopimazine mesylate (e.g.,metopimazine mesylate Crystal Form A or metopimazine mesylate CrystalForm B) is administered for less than five days.

Exemplary Combination Therapies

In some embodiments, the method comprises co-administration of anadditional agent. Additional agents may be: small molecules,nutraceuticals, vitamins, e.g., vitamin D, drugs, pro-drugs, biologics,peptides, peptide mimetics, antibodies, antibody fragments, cell ortissue transplants, vaccines, polynucleotides, DNA molecules, RNAmolecules, (i.e.-siRNA, miRNA), antibodies conjugated to drugs, toxins,fusion proteins. Agents may be delivered by vectors, including but notlimited to: plasmid vectors, viral vectors, non-viral vectors, liposomalformulations, nanoparticle formulations, toxins, therapeuticradioisotopes, etc.

In some embodiments, a method of the application comprisesco-administration of a peripherally restricted dopamine decarboxylaseinhibitor and a pharmaceutical composition as described herein. Forexample, an application method may comprise co-administration ofcarbidopa and a pharmaceutical composition as described herein.

The additional agent can be an agent for use in the treatment of anenteric nervous system disorder. In some embodiments, the additionalagent is an additional anti-emetic agent (e.g., used for the treatmentof nausea and/or vomiting). The additional anti-emetic agent can be, byway of non-limiting example only, a 5-HT3 receptor antagonist, adopamine receptor antagonist, an NK1 receptor antagonist, anantihistamine, a cannabinoid, a benzodiazepine, an anticholinergicagent, a steroid, or other anti-emetic. Exemplary 5-HT3 receptorantagonists include, but are not limited to, Odansetron, Tropisetron,Granisetron, Palonosetron, Dolasetron. Exemplary dopamine receptorantagonists include, e.g., Metoclopramide (Reglan), Domperidone(Motilium), Olanzapine (Zyprexa) Droperidol, haloperidol,chlorpromazine, promethazine, prochlorperazine, Alizapride,Prochlorperazine, Sulpiride. Exemplary NK1 receptor antagonists include,e.g., Aprepitant, Tradipitant or Casopitant. Exemplary antihistaminesinclude, e.g., Cyclizine, Diphenhydramine (Benadryl), Dimenhydrinate(Gravol, Dramamine), Doxylamine, Meclozine (Bonine, Antivert),Promethazine (Pentazine, Phenergan, Promacot), and Hydroxyzine(Vistaril), Cimetidine, Famotidine, Lafutidine, Nizatidine, Ranitidine,Roxatidine, Tiotidine. Exemplary cannabinoids include, e.g., Cannabis,Sativex, tetrahydrocannabinol, Dronabinol, and synthetic cannabinoidssuch as Nabilone. Exemplary benzodiazepines include, e.g., midazolam orlorazepam. Exemplary anticholinergic agents include, e.g., scopolamine.Other exemplary anti-emetics include, e.g., Trimethobenzamide, Ginger,Emetrol, Propofol, Peppermint, erythromycin, Muscimol, botulinum toxin A(e.g., injected into the stomach to relax the pyloric muscle), andAjwain.

The additional agent can be an agent for treatment of another disease orclinical syndrome associated with gastroparesis. Exemplary otherdiseases and clinical syndromes are described herein. The additionalagent can be an agent for treatment of diabetes. Exemplary agents forthe treatment of diabetes include, e.g., insulin. Other agents for thetreatment of diabetes are described in, for example, U.S. Pat. Nos.6,274,549, 8,349,818, 6,184,209, US Patent Application Publication No.US20070129307, and PCT Application Publication No. WO/2004/082667A1, allof which are hereby incorporated by reference.

The additional agent can be for treatment of upper and lower dysmotilitydisorders associated with Parkinson's disease. The additional agent canbe for treatment of Parkinson's disease. Exemplary agents for thetreatment of Parkinson's disease include, e.g., dopaminergic agents,MAO-A or B inhibitors such as, e.g., selegiline, COMT inhibitors such asentacapone, amantadine, stem cell transplant, and neuroprotectiveagents. Exemplary dopaminergic agents include, but are not limited tolevodopa, bromocriptine, pergolide, pramipexole, cabergoline,ropinorole, apomorphine or a combination thereof.

The additional agent can be for treatment of hypothyroidism,hyperthyroidism, or hyperparathyroidism. Exemplary agents for thetreatment of such diseases include, e.g., beta-adrenergic blockers(“beta blockers”), levothyroxine calcimimetics, estrogen, progesterone,bisphosphonates.

The additional agent can be for treatment of adrenal insufficiency.Exemplary agents for treatment of adrenal insufficiency include, e.g.,corticosteroid hormones (for example, aldosterone, fludrocortisones, andcortisol).

The additional agent can be for treatment of gastroesophageal reflux.Exemplary agents for treatment of gastroesophageal reflux include, e.g.,antacids such as, for example, proton pump inhibitors such asomeprazole, H2 receptor antagonists such as ranitidine, antacids,mosapride, sucralfate, and baclofen.

The additional agent can be for treatment of scleroderma. For example,the additional agent can be D-penicillamine, colchicine, PUVA, relaxin,cyclosporine, and EPA (omega-3 oil derivative), immunosupressants suchas, e.g., methotrexate, cyclophosphamide, azathioprine, andmycophenolate. The additional agent can be for treatment ofpolymyositis. For example, the additional agent can be a corticosteroid,e.g., prednisone, or can be an immunosuppressant.

The additional agent can be for treatment of muscular dystrophy. Forexample, the additional agent can be, e.g., a glucocorticoid receptorantagonist. Exemplary glucocorticoid receptor antagonists include, butare not limited to, mifepristone,11β-(4-dimethylaminoethoxyphenyl)-17α-propynyl-17β-hydroxy-4,9estradien-3-one,17β-hydroxy-17α-19-(4-methylphenyl)androsta-4,9(11)-dien-3-one,4α(S)-Benzyl-2(R)-prop-1-ynyl-1,2,3,4,4α,9,10,10α(R)-octahydro-phenanthrene-2,7-dioland4α(S)-Benzyl-2(R)-chloroethynyl-1,2,3,4,4α,9,10,10α(R)-octahydro-phenanthrene-2,7-diol,and (11β,17β)-11-(1,3-benzodioxo-5-yl)-17-hydroxy-17-(1-propynyl)estra-4,9-dien-3-one.

The additional agent can be for treatment of amyloidosis. For example,the additional agent can be an amyloid beta sheet mimic, an antioxidant,molecular chaperone, or other agent. Exemplary agents for the treatmentof amyloidosis are described in, e.g., WO/2008/141074. Exemplarymolecular chaperones include, e.g., HSP60, HSP70, HSP90, HSP100, BiP,GRP94, GRP170, calnexin and calreticulin, Protein disulfide isomerase(PDI), Peptidyl prolyl cis-trans-isomerase (PPI), trimethylamine N-oxide(TMAO), betaine, glycine betaine, glycero-phosphorylcholine,carbohydrates such as, e.g., glycerol, sorbitol, arabitol, myo-inositoland trehalose, choline, 4-Phenyl butyric acid, and taurine-conjugatedursodeoxycholic acid.

The additional agent can be for treatment of chronic idiopathicpseudoobstruction. For example, the additional agent can bePrucalopride, Pyridostigmine, Metoclopramide, cisapride, linaclotide,octreotide, cannabinoids, and erythromycin.

The additional agent can be for treatment of dermatomyositis. Forexample, the additional agent can be Prednisolone, Methotrexate,Mycophenolate (CellCept/Myfortic), intravenous immunoglobulins,Azathioprine (Imuran), Cyclophosphamide, Rituximab, and Acthar Gel.

The additional agent can be for treatment of systemic lupuserytematosus. For example, the additional agent can be renal transplant,corticosteroids, immunosupressants, Hydroxychloroquine,Cyclophosphamide, Mycophenolic acid, immunosupressants, analgesics,intravenous immunoglobins, and the like.

The additional agent can be for treatment of anorexia and/or bulimia.For example, the additional agent can be olanzapine, a tricyclicantidepressant, an MAO inhibitor, mianserin, a selective serotoninreuptake inhibitor, e.g., fluoxetine, lithium carbonate, trazodone, andbupropion, phenytoin, carbamazepine, and valproic acid, opiateantagonists such as, e.g., naloxone and naltrexone, and topiramate.

The additional agent can be for treatment of depression. For example,the additional agent can be a selective serotonin reuptake inhibitor, aserotonin and norepinephrine reuptake inhibitor, bupropion, a tricyclicantidepressant, a monoamine oxidase inhibitor, and the like. Theadditional agent can be for treatment of paraneoplastic syndrome. Theadditional agent can be for treatment of a high cervical cord lesion.For example, the additional agent can be a corticosteroid or otheranti-inflammatory medication. The additional agent can be for treatmentof multiple sclerosis. For example, the additional agent can beinterferon beta-1b, interferon beta-1a, Glatiramer acetate,Mitoxantrone, natalizumab, fingolimod, teriflunomide, or cladribine.

The additional therapeutic agent can be selected from the groupconsisting of serotonin agonists, serotonin antagonists, selectiveserotonin reuptake inhibitors, anticonvulsants, opioid receptoragonists, bradykinin receptor antagonists, NK receptor antagonists,adrenergic receptor agonists, benzodiazepines, gonadotropin-releasinghormone analogues, calcium channel blockers, and somatostatin analogs.

Dosages of the additional agent and of a pharmaceutical composition asdescribed herein for use in the treatment of an enteric nervous systemdisorder can vary depending on the type of additional therapeutic agentemployed, on the disease or condition being treated and so forth.Sub-therapeutic amounts of one or both of the additional agent and thepharmaceutical composition as described herein can be used. Thesub-therapeutic amount of one or both of the additional agent and thepharmaceutical composition as described herein can be a synergisticallyeffective amount. Therapeutically effective amounts of one or both ofthe additional agent and the pharmaceutical composition as describedherein can be used. The pharmaceutical composition as described hereinand the additional agent may be administered either simultaneously orsequentially. If administered sequentially, the attending physician orcaretaker can decide on the appropriate sequence of administering thepharmaceutical composition as described herein and the additionaltherapeutic agent.

In some embodiments, a method comprising administering any of thepharmaceutical compositions described herein further comprisescombination therapy with an additional therapeutic regimen. Theadditional therapeutic regimen can comprise implantation of a medicaldevice. The medical device can be implanted in the stomach and/orabdomen, e.g., in the duodenum. The medical device can be an electricaldevice. The medical device can be a pacemaker. Such a pacemaker canutilize electrical current to induce stomach and/or duodenalcontractions, thereby promoting gastrointestinal motility. Such medicaldevices, and methods of using them, are disclosed in U.S. Pat. No.8,095,218, hereby incorporated by reference.

Embodiments of the application are further described in detail byreference to the following examples. These examples are provided for thepurpose of illustration only, and are not intended to be limiting unlessotherwise specified. Thus, the application should in no way be construedas being limited to the following examples, but rather, should beconstrued to encompass any and all variations which become evident as aresult of the teaching provided herein.

EXAMPLES

The following examples are offered to illustrate but not to limit theapplication.

Example 1: Synthesis of Metopimazine Mesylate Crystal Form A

One of skill in the art will recognize that the following syntheticreactions and schemes may be modified by choice of suitable conditionsand reagents in order to access metopimazine mesylate,1-(3-(2-(methylsulfonyl)-10H-phenothiazin-10-yl)propyl)piperidine-4-carboxamidemethanesulfonic acid, from metopimazine,1-(3-(2-(methylsulfonyl)-10H-phenothiazin-10-yl)propyl)piperidine-4-carboxamide.Metopimazine, and methods of making metopimazine, are described in DE1092476, hereby incorporated by reference. Metopimazine can be obtainedfrom a variety of commercial sources (CAS registry number 0014008-44-7).By way of example only, metopimazine can be obtained from ABI Chemicals(#AC2A05HFH), AKos (#AKOS005065914), Biochempartner (#BCP9000716),Molport (#MolPort-003-808-703), Santa Cruz Biotechnology (#sc-211901),and Tractus Company Limited (#TX-013443).

To metopimazine (50 g) was added dimethyl sulfoxide (DMSO) (150 mL)followed by methanesulfonic acid (MsOH) (11.3 g) over 10 min at 20-25°C. to give a clear solution. Acetone (50 mL) was then added and thesolution was filtered over a filter paper. The filtrate was warmed to68° C. and charged with acetone (175 mL) over 15 min at 68° C. Thesolution was then cooled to 60° C. over 30 minutes and then agitated at60° C. for one hour at which time the solution became cloudy. The slurrywas cooled to 0° C. over 1.5 hours and then agitated at 0° C. for 1hour. The solid was collected by filtration and the filter cakereslurried with acetone (200 mL) for 30 minutes. The solid was collectedby filtration and the remaining filter cake again reslurried withacetone (200 mL) for 30 minutes. The solid was again collected byfiltration. The filter cake was dried under vacuum at 50° C. for 6 hoursto afford a yellow solid, metopimazine mesylate Crystal Form A, 40 g,66% yield.

Similarly, a large scale preparation was performed as follows. Tometopimazine (1500 g) was added DMSO (4.5 L) followed by MsOH (341 g)over 30 min at 20-25° C. to give a clear solution. Acetone (1.5 L) wasthen added and the solution was filtered over a filter paper. Thefiltrate was warmed to 68° C. and charged with acetone (5.25 L) over 30min at 68° C. Seed crystals (15 g) were added to the solution. Thecloudy solution was then agitated at 68° C. for one hour. The slurry wascooled to 0° C. over 6 hours and the mixture agitated at 0° C. for 14hour. The solid was collected by filtration and the filter cake washedwith acetone (4.5 L). The filter cake was agitated with acetone (6 L)for 30 minutes. The solid was collected by filtration, and the filtercake was agitated with acetone (6 L) for 30 minutes. The solid wascollected by filtration. The filter cake was dried under vacuum at 50°C. for 7 hours to afford a yellow solid, metopimazine mesylate CrystalForm A, 1558 g, 85% yield.

The structure of metopimazine mesylate was confirmed by high resolutionmass spectrometry ([M+H]+=446.16), ¹H NMR (Table 3), and ¹³C NMR (Table4).

TABLE 3 ¹H NMR of Metopimazine Mesylate; 400 MHz ¹HNMR; DMSO-d6 ChemicalShift Coupling Constant (ppm) Integration Multiplicity (J, Hz) 9.15 1 Hs — 6.91-7.48 9 H m — 4.06 2 H t  6.6 3.46 2 H d 11.2 3.41 3 H s — 3.172 H m — 2.88 2 H dd 22.8, 11.2 2.37 4 H m — 2.08 2 H m — 1.90 2 H m —1.72 2 H dd 24.4, 12.0

TABLE 4 ¹³C NMR of Metopimazine Mesylate; 400 MHz ¹³CNMR; DMSO-d6Chemical Shift Multiplicity 174.80 s 145.41 s 143.38 s 140.28 s 131.31 s128.26 s 127.85 s 127.56 s 123.68 s 122.99 s 121.12 s 116.74 s 113.59 s53.80 s 51.41 s 43.93 s 43.49 s 38.53 s 25.86 s 21.26 s

The structure of the single crystal was determined successfully. Thecrystal system was Monoclinic, the space group was Pn. The unit celldimensions of the structure were as follows: a=11.90502(6) Å,b=5.57773(3) Å, c=19.47543(12) Å, α=90°, β=103.5908(6)°, γ=90°,V=1257.014(13) Å3. The asymmetric unit was found to contain oneMetopimazine cation and one Mesylate anion, which indicated Form A is ananhydrate. The final refinement parameters are listed below in Table 5.

TABLE 5 Crystallographic data and refinement parameters Identificationcode 818114-01-A Empirical formula C₂₃H₃₁N₃O₆S₃ Formula weight 541.69Temperature 100.01(10) K Wavelength CuKα (λ = 1.54184 Å) Crystal system,space group Monoclinic, Pn Unit cell dimensions a = 11.90502(6) Å b =5.57773(3) Å c = 19.47543(12) Å α = 90° β = 103.5908(6)° γ = 90° Volume1257.014(13) Å³ Z, Calculated density 2, 1.431 g/cm³ Absorptioncoefficient 3.077 mm⁻¹ F(000) 572.0 Crystal size 0.12 × 0.08 × 0.05 mm³2 Theta range for data 7.964 to 149.606 collection Limiting indices −14≤ h ≤ 14 −6 ≤ k ≤ 5 −24 ≤ l ≤ 23 Reflections collected/ 41976/4970[R_(int) = 0.0425, Independent reflections R_(sigma) = 0.0215]Refinement method Full-matrix least-squares on F²Data/restraints/parameters 4970/2/330 Goodness-of-fit on F² 1.046 FinalR indices [I ≥ 2sigma(I)] R₁ = 0.0225, wR₂ = 0.0557 Final R indices [alldata] R₁ = 0.0230, wR₂ = 0.0561 Largest diff. peak and hole 0.17/−0.31e.Å⁻³

The peak list of the calculated XRPD of the single crystal forMetopimazine Mesylate Crystal Form A is provided in Table 6.

TABLE 6 Peak List of the Calculated XRPD of the Single Crystal Pos.Height Pos. Height Pos. Height Pos. Height [°2Th.) [cts] [°2Th.] [cts][°2Th.] [cts] [°2Th.] [cts] 7.957 82.639 21.845 4066.813 28.902 450.32734.203 679.729 9.336 2364.303 22.129 340.111 29.408 292.149 34.451214.356 9.841 143.466 22.579 215.487 29.648 385.100 34.883 276.07814.310 238.385 23.364 493.197 29.823 152.139 35.141 264.082 15.3014263.465 23.718 472.990 30.079 108.698 35.270 273.631 15.953 6407.84624.028 2541.677 30.723 885.873 35.759 193.775 16.555 1744.832 24.46910199.890 30.887 972.559 36.027 936.252 17.505 1459.676 24.637 3353.19831.403 403.286 36.528 111.915 17.781 4685.051 25.447 680.649 31.892742.574 36.896 648.189 18.451 865.592 26.412 1432.003 32.130 481.24137.494 276.960 18.727 4592.584 26.645 695.484 32.422 283.382 37.994541.559 19.119 6048.643 26.975 274.768 32.575 162.015 38.137 408.05719.759 691.551 27.574 219.672 33.107 579.165 38.798 73.631 20.8274974.073 28.004 986.973 33.470 655.390 39.461 393.184 21.251 7494.35428.208 1092.305 33.617 368.145 39.779 580.681 21.433 4760.087 28.467377.833 33.864 416.154 / /

For XRPD analysis, PANalytical X-ray powder diffract meters were used.Samples were prepared by putting a layer of sample (approx. 5 mg) on thecenter of a silicon wafer. The XRPD parameters used are listed in Table7. The XRPD pattern is provide in FIG. 1 , and the peaks provided inTable 1 above.

TABLE 7 Parameters for XRPD test Parameters X′ Pert3 Mode Reflectionmode X-Ray wavelength Cu*, Kα, Kα1 (Å): 1.540598, Kα2 (Å): 1.544426Kα2/Kα1 intensity ratio: 0.50 X-Ray tube setting 45 kV, 40 mA Divergenceslit ⅛° Scan mode Continuous Scan range (2Θ/°) 3°-40° Step size (2Θ/°)46.7 Scan step time (s) 0.0263 Test Time (s) 5 min 04 s *Filter:Beta-filter nickel

TGA data were collected using a TA Q5500 TGA from TA Instruments and DSCwas performed using a TA Q2500 DSC from TA Instruments. Detailedparameters used are listed in Table 8. Sample was prepared by addingsample (approximately 2 mg) in the pan. The TGA plot is provided in FIG.2 . Metopimazine mesylate Crystal Form A exhibited minimal weight lossby TGA (0.4% up to 150.0° C.). The DSC plot is provided in FIG. 3 .Metopimazine mesylate Crystal Form A exhibited a clear melt with onsetat 209.9° C. (melt=213.1° C.; enthalpy=97.47 J/g).

TABLE 8 Parameters for TGA and DSC test Parameters TGA DSC Method RampRamp Sample pan Aluminum, open Aluminum, crimped Temperature RT-350° C.RT-300° C. Heating rate 10° C./min 10° C./min Purge gas N₂ N₂

Example 2: Synthesis of Metopimazine Mesylate Crystal Form B

A glass beaker containing a thin layer of metopimazine mesylate CrystalForm A (10 g) was allowed to sit at room temperature and 100% relativehumidity for approximately 3-5 days to provide metopimazine mesylateCrystal Form B as an off-white solid. The structure of metopimazinemesylate Crystal Form B was confirmed by ¹H NMR (Table 9).

TABLE 9 ¹H NMR of Metopimazine Mesylate Crystal Form B; 400 MHz ¹HNMR;DMSO-d6 Chemical Shift Coupling Constant (ppm) Integration Multiplicity(J, Hz) 8.96 1 H s — 6.91-7.52 9 H m — 4.06 2 H t  6.7 3.46 2 H d 11.43.24 3 H s — 3.15 2 H m — 2.89 2 H dd 10.6, 22.9 2.33 4 H m — 2.09 2 H m— 1.89 2 H m — 1.69 2 H dd 14.6, 27.4

For XRPD analysis, PANalytical X-ray powder diffract meters were used.Sample was prepared by putting a layer of sample (approx. 5 mg) on thecenter of a silicon wafer. The XRPD parameters used are listed in Table6 above. The XRPD pattern is provide in FIG. 4 , and the peaks providedin Table 2 above.

TGA data were collected using a TA Q5500 TGA from TA Instruments and DSCwas performed using a TG Q2000 DSC from TA Instruments. Detailedparameters used are listed in Table 7 above. Sample was prepared byadding sample (approximately 2 mg) in the pan. The TGA/DSC plot isprovided in FIG. 5 . A weight loss of 5.8% was observed up to 180° C.,and two endothermic peaks at 123.5 and 208.6° C. (onset temperature)(melt=126.1° C. and 211.2° C., respectively; enthalpy=83.47 J/g and84.48 J/g, respectively) and one exothermic peak at 144.6° C. (peaktemperature) were observed.

Example 3: Pharmacokinetic Analysis of Metopimazine Mesylate CrystalForm A

A clinical comparative pharmacokinetic study was performed to understandthe pharmacokinetic profile of metopimazine mesylate Crystal Form A incomparison to the free base of metopimazine. This study was as a3-period, cross-over design with 3 administrations of single doses: oralformulation of metopimazine mesylate Crystal Form A fasting, oralformulation of metopimazine mesylate Crystal Form A after a high-fatbreakfast, and oral formulation of metopimazine free base fasting, witha wash-out period of 48 hours between each administration. Fifteensubjects were enrolled and received each of the 3 treatment. Plasmasamples from each subject were analyzed for various pharmacokineticparameters. Mixed model repeated measures (MMRM) analysis was performedon each sample. The comparison of metopimazine mesylate Form A andmetopimazine free base showed that T_(max) values for metopimazinemesylate Form A had a statistically significantly lower variance thanmetopimazine free base. The results are shown in Table 10 below.

TABLE 10 T_(max) Analysis Treatment Parameter T_(max) (h) Metopimazinefree base, Mean 1.27 15 mg, n = 15; fasted SD 0.98 CV % 77.33 Min 0.50Median 1.00 Max 4.00 Metopimazine mesylate Mean 0.87 Crystal Form A, SD0.30***¹ 15 mg, n = 15; fasted CV % 34.25 Min 0.50 Median 0.75 Max 1.50¹p < 0.0001***

The above results demonstrate that metopimazine mesylate Crystal Form Aprovides a more predictable onset of action as compared to metopimazinefree base. The lower variance in T_(max) for metopimazine mesylateCrystal Form A provides an important benefit to the population ofsubjects suffering from gastroparesis as that population requires atreatment that can be taken before meal time so as to reduce thesymptoms that invariably are worsened by eating.

The second objective of this study was to compare the pharmacokineticsof metopimazine mesylate Crystal Form A administered as an oraladministration of a single dose of 15 mg orally in 15 human subjectseither in a fasted state or after a high fat breakfast. Plasma samplesfrom each subject were analyzed for various pharmacokinetic parameters.The geometric mean difference in C_(max) was slightly but significantlylower, whereas there was not statistical difference in the geometricmean AUC. Both C_(max) and AUC are well within the 90% confidenceinterval. The results are shown in Table 11 below.

A minor reduction in C_(max) of approximately 15% was seen whenmetopimazine mesylate Crystal Form A was administered with food, butthere was no notable change in AUC (well within the 90% upper and lowerintervals which define bioequivalence). This slight difference inC_(max) is not of clinical significance (FDA Guidance for the industry:Food-Effect Bioavailability and Fed Bioequivalence Studies). Theseresults are in contrast with previously published data indicating a foodeffect for metopimazine free base which resulted in a 58% reduction inC_(max) and a 23% reduction in AUC following administration ofmetopimazine free base before and after a high fat breakfast (Herrstedtet al. 1990).

TABLE 11 C_(max) and AUC Analysis C_(max) AUC_(0-inf) Geometric LeastGeometric Least Square Mean Square Mean Treatment (GLSM) (ng/mL) (GLSM)(ng · h/mL) Metopimazine Mesylate 18.16 63.96 Crystal Form A 15 mg n =15; fasted Metopimazine Mesylate 15.26 59.89 Crystal Form A 15 mg n =15; fed high fat breakfast (1030 kcal, 16% protein, 61% fat, 23%carbohydrate) Ratio fasted vs fed (%) 84.07 93.63 Lower CI % 63.8286.00* Upper CI % 110.75 101.93* *Bioequivalence

The lack of food effect for metopimazine mesylate Crystal Form Aprovides a benefit to the population of subjects suffering fromgastroparesis as that population displays delayed gastric emptying andresidual gastric food contents for extended periods of time which couldexacerbate the PK variability of a drug sensitive to food such asmetopimazine free base.

While preferred embodiments of the present application have been shownand described herein, it will be obvious to those skilled in the artthat such embodiments are provided by way of example only. Numerousvariations, changes, and substitutions will now occur to those skilledin the art without departing from the application. It should beunderstood that various alternatives to the embodiments of theapplication described herein may be employed in practicing theapplication. It is intended that the following claims define the scopeof the application and that methods and structures within the scope ofthese claims and their equivalents be covered thereby.

INCORPORATION BY REFERENCE

All references cited in this application, and their references, areincorporated by reference herein in their entirety where appropriate forteachings of additional or alternative details, features, and/ortechnical background.

1-24. (canceled)
 25. A crystalline form of metopimazine mesylatecharacterized by an X-ray powder diffraction pattern comprising two ormore of the following 2θ values: 4.64°, 8.57°, 10.71°, 11.12°, 11.75°,12.51°, 13.47°, 13.87°, 15.82°, 16.30°, 16.90°, 17.29°, 17.60°, 17.89°,18.42°, 18.88°, 19.16°, 20.00°, 20.66°, 21.44°, 22.02°, 22.47°, 23.21°,23.61°, 24.79°, 25.51°, 26.09°, 26.57°, 27.12°, 27.77°, 28.39°. 28.78°,32.94°, and 36.31°±0.2°.
 26. The crystalline form of claim 25,characterized by an X-ray powder diffraction pattern comprising two ormore of the following 2θ values: 4.64°, 10.71°, 11.12°, 16.30°, 16.90°,17.89°, 20.00°, and 27.12±0.2°.
 27. The crystalline form of claim 26,characterized by an X-ray powder diffraction pattern comprising three ormore of the following 2θ values: 4.64°, 10.71°, 11.12°, 16.30°, 16.90°,17.89°, 20.00°, and 27.12±0.2°.
 28. The crystalline form of claim 25,characterized by an X-ray powder diffraction pattern comprising peaks atthe following 2θ values: 16.90° and 20.00°±0.2°.
 29. The crystallineform of claim 25, characterized by an X-ray powder diffraction patterncomprising peaks at the following 2θ values: 16.30°, 16.90°, and20.00°±0.2°.
 30. A crystalline form of metopimazine mesylatecharacterized by a differential scanning calorimetry pattern comprisinga first endothermic peak comprising an onset temperature range of 122°C. to 125° C., a second endothermic peak comprising an onset temperaturerange of 207° C. to 210° C., and a single exothermic peak comprising apeak temperature range of 143° C. to 146° C.
 31. The crystalline form ofclaim 30, wherein the first endothermic peak comprises an onsettemperature range of 123° C. to 124° C.
 32. The crystalline form ofclaim 30, wherein the first endothermic peak comprises a peaktemperature range of 125° C. to 127° C.
 33. The crystalline form ofclaim 30, wherein the first endothermic peak comprises an enthalpy oftransition of 81-86 J/g.
 34. The crystalline form of claim 30, whereinthe second endothermic peak comprises an onset temperature range of 208°C. to 209° C.
 35. The crystalline form of claim 30, wherein the secondendothermic peak comprises a peak temperature range of 210° C. to 212°C.
 36. The crystalline form of claim 30, wherein the second endothermicpeak comprises an enthalpy of transition of 82-87 J/g.
 37. A crystallineform of metopimazine mesylate characterized by a thermogravimetricanalysis profile comprising a total weight loss of between 5.5-6% up to180.0° C.
 38. A pharmaceutical composition comprising the crystallineform of claim 25 and a pharmaceutically acceptable excipient.
 39. Thepharmaceutical composition of claim 38, wherein the pharmaceuticalcomposition comprises less than 10 wt. % of other crystalline forms ofmetopimazine mesylate.
 40. The pharmaceutical composition of claim 38,wherein the pharmaceutical composition comprises less than 1 wt. % ofother crystalline forms of metopimazinemesylate.
 41. The pharmaceuticalcomposition of claim 38, wherein the composition comprises less than 10wt. % of amorphous forms of metopimazine mesylate.
 42. Thepharmaceutical composition of claim 38, wherein the compositioncomprises less than 1 wt. % of amorphous forms of metopimazine mesylate.43. The pharmaceutical composition of claim 38, wherein thepharmaceutical composition is suitable for administering orally,intraduodenally, intracolonically, enterally, topically, intranasally,non-orally, buccally, sublingually, by inhalation, or rectally.
 44. Thepharmaceutical composition of claim 43, wherein the composition issuitable for administering orally.
 45. The pharmaceutical composition ofclaim 43, wherein the composition is suitable for administeringsublingually.
 46. The pharmaceutical composition of claim 38, whereinthe pharmaceutical composition is formulated as a tablet, a capsule, apaste, a powder, a suspension, a suppository, an extended-releaseformulation, or a modified-release formulation.
 47. The pharmaceuticalcomposition of claim 46, wherein the composition is formulated as anextended release formulation.
 48. The pharmaceutical formulation ofclaim 46, wherein the composition is formulated as a capsule.